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Archive for the ‘Male Genetics’ Category

Genetics of Prostate Cancer (PDQ)Health Professional …

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The public health burden of prostate cancer is substantial. A total of 180,890 new cases of prostate cancer and 26,120 deaths from the disease are anticipated in the United States in 2016, making it the most frequent nondermatologic cancer among U.S. males.[1] A mans lifetime risk of prostate cancer is one in seven. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patients life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate than white men.[4] African American men have been reported to have more than twice the rate of prostate cancerspecific death compared with non-Hispanic white men.[1] Differences in race-specific prostate cancer survival estimates may be narrowing over time.[5]

These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[6] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[7] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, and there is increasing knowledge of the molecular genetics of the disease, although much of what is known is not yet clinically actionable. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[8]

The three most important recognized risk factors for prostate cancer in the United States are:

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 325 for men 49 years or younger, 1 in 48 for men aged 50 through 59 years, 1 in 17 for men aged 60 through 69 years, and 1 in 10 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]

Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer is increasing, and there is evidence that some cases may be more aggressive.[9] Because early-onset cancers may result from germline mutations, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[10,11] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[12]

Prostate cancer is highly heritable; the inherited risk of prostate cancer has been estimated to be as high as 60%.[13] As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[14-18] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[15,19,20] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[16-20] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[21]

Although some of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[22-24] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)[25]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[26] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.052.20) with an affected father only, 2.96 (95% CI, 2.803.13) with an affected brother only, and 8.51 (95% CI, 6.1311.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.2625.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[27] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR, 1.7; 95% CI, 1.03.0; multivariate RR, 1.7; 95% CI, 0.93.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR, 5.8; 95% CI, 2.414.0).[22] Analysis of data from the Women's Health Initiative also showed that a family history of prostate cancer was associated with an increase in the risk of postmenopausal breast cancer (adjusted HR, 1.14; 95% CI, 1.021.26).[28] Further analyses showed that breast cancer risk was associated with a family history of both breast and prostate cancers; the risk was higher in black women than in white women. Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[22,29] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[30] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[31-34] (Refer to the BRCA1 and BRCA2 section of this summary for more information.)

Prostate cancer clusters with particular intensity in some families. Highly penetrant genetic variants are thought to be associated with prostate cancer risk in these families. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age at diagnosis and specific family cancer history patterns.[35,36] Individuals meeting the following criteria may warrant referral for genetic consultation:[35-38]

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[39] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.93.3) with adjustment for age and ethnicity.[39]

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone before puberty do not develop prostate cancer.[40] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[41] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[42] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[43]

(Refer to the PDQ summary on Prostate Cancer Prevention for more information about nongenetic modifiers of prostate cancer risk in the general population.)

The SEER Cancer Registries assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.015.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed before age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus; and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[44]

A review of more than 441,000 men diagnosed with prostate cancer between 1992 and 2010 demonstrated similar findings, with an overall reduction in the risk of being diagnosed with a second primary cancer. This study also examined the risk of second primary cancers in 44,310 men (10%) by treatment modality for localized cancer. The study suggested that men who received radiation therapy had increases in bladder (standardized incidence ratio [SIR], 1.42) and rectal cancer risk (SIR, 1.70) compared with those who did not receive radiation therapy (SIRbladder, 0.76; SIRrectal, 0.74).[45]

The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors, including treatment modality. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[44]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the RR was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[46]

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[47-49]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (SIR, 1.9; 95% CI, 1.03.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer sitespecific disorder.[50]

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic (MZ) and dizygotic (DZ) twin pairs in Scandinavia concluded that 58% (95% CI, 5263) of prostate cancer risk may be accounted for by heritable factors.[13] Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins (mean, 3.8 years in MZ twins vs. 6.5 years in DZ twins). This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs.[51] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[15] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[52]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[53-55] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[51] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [56-59] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (

Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, are moderately to highly penetrant in families, and have large (e.g., relative risk >2.0) effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have low to modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a mans lifetime risk of prostate cancer is one in seven,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. There are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease, although current advances in the understanding of molecular phenotypes of prostate cancer may be informative in identifying inherited prostate cancer. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score 7, PSA 20 ng/mL) in an affected man.[5-7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate canceraffected individuals. Conflicting evidence exists regarding the linkage to some of the loci described above. Data on the proposed phenotype associated with each locus are also limited, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (2) logarithm of the odds (LOD) score, heterogeneity LOD (HLOD) score, or summary LOD score:

The chromosomal region 19q has also been found to be associated with prostate cancer, although specific LOD scores have not been described.[8,11,95]

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint HLOD scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[92,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[111] Further study including a larger number of African American families is needed to confirm these findings.

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (HLOD score = 2.18) and 22q12.3-q13.1 (HLOD score = 1.90).[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[107] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[112] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.093.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.

In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[113] A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[114] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 hereditary prostate cancer families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[113]

Linkage to chromosome 17q21-22 and subsequent fine-mapping and targeted sequencing have identified recurrent mutations in the HOXB13 gene that account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. Multiple studies have confirmed the association between the G84E mutation in HOXB13 and prostate cancer risk. (Refer to the HOXB13 section of this summary for more information.) The clinical utility of testing for HOXB13 mutations has not yet been defined, but studies are ongoing to define the clinical role. For example, a study evaluated 948 unselected men scheduled for prostate biopsy. The G84E mutation was found in three men (0.3%) who had prostate cancer detected on biopsy, although none of the 301 men who had a family history of prostate cancer carried the mutation.[115] Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional moderately to highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.[116]

A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[117,118]

Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[117,118]

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[120] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[121]

Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[122,123] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[120,122-132] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.11.3) and short GGN length (OR, 1.3; 95% CI, 1.11.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[133] Subsequently, the large multiethnic cohort study of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[134] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.081.69; P = .03).[135]

An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Mens Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[136] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[134,137,138] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[139] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[140] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[141]

Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone (DHT) by 5-alpha-reductase type II.[142] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[143,144]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[145] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[142,146] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[120,142] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[147] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.012.08; OR, 1.49; 95% CI, 1.032.15).[135] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.092.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.142.68).[148] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[149]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.350.88; OR, 0.57; 95% CI, 0.360.90; OR, 0.55; 95% CI, 0.350.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.942.63).[150] Additional studies are needed to confirm these findings.

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[151] This study awaits replication.

Germline mutations in the tumor suppressor gene E-cadherin (also called CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene.[152] Because somatic mutations in E-cadherin have been implicated in the development of invasive malignancies in a number of different cancers,[153] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.111.60). However, the authors of the study noted that there are sources of bias in the dataset, stemming mostly from the small sample sizes of individual cohorts.[154] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[155] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[156] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[157-161] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[162] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.330.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[163] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[164] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[165]

Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[166] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[167] Therefore, the biologic basis of the various associations identified requires further study.

Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for hereditary prostate cancer susceptibility has not been established.

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[178] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[179,180]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[182] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[179] (Refer to the GWAS section of this summary for more information.)

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[183] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[184,185] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to scan the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million to 5 million SNPs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signalsin which allele frequencies deviate significantly in case compared to control populationsare validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently when standard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P

To date, approximately 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4).[189] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[192]

In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70-73,80-83,193] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73-75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54128.62 Mb, region 2 at 128.14128.28 Mb, and region 3 (containing rs6983267) at 128.47128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]

Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[206] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are included in Table 5. The association between risk and allele status for each variant listed in Table 5 reached genome-wide statistical significance in more than one independent cohort.

The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[208] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.

Some of the risk variants identified in Table 5 have also been found to confer risk in men of European ancestry. These include rs16901979, rs6983267, and rs1447295 at 8q24 in African Americans and rs13254738 in Japanese populations. Additionally, the Japanese rs4430796 at 17q12 and rs2660753 at 3p12 have also been observed in men of European ancestry. However, the vast majority of the variants identified in these studies reveal novel variants that are unique to that specific ethnic population. These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.936.80; P = 1.20 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.6224.72; P = 1.29 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.646.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.835.33).[214]

However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[215] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[216]

Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[217]

In another study, 49 risk SNPs were genotyped in 2,696 Swedish men, and a polygenic risk score was calculated. On the basis of their genetic risk scores, 172 men aged 50 to 69 years with PSA levels of 1 to 3 ng/mL underwent biopsy. Prostate cancer was diagnosed in 27% of these individuals, and 6% had Gleason 7 or higher disease.[218] The utility of this strategy for identifying who should undergo prostate biopsy is yet to be determined.

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[216] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have poor discriminative ability to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional common risk alleles (alleles carried by >1%5% of individuals within the population).[219]

GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.

Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:

The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[222] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[223-225] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[226] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[224,226] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.

Additional insights are emerging regarding the potential interaction between SNPs identified from GWAS and prostate cancer susceptibility gene regulation. One study found that a SNP at 6q22 lies within a binding region for HOXB13. Through multiple functional approaches, the T allele of this SNP (rs339331) was found to enhance binding of HOXB13, leading to allele-specific upregulation of RFX6, which correlates with prostate cancer progression and severity.[227] Thus, this study supports the hypothesis that risk alleles identified from GWAS may play a role in regulating or modifying gene expression and therefore impact prostate cancer risk.

A 2012 study used a novel approach to identify polymorphisms associated with risk.[228] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13a locus previously implicated in cancer developmentassociated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.131.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[229] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Prostate cancer is clinically heterogeneous. Many cases are indolent and are successfully managed with observation alone. Other cases are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed, as sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers since they are present, easily detectable, and static throughout life. Several studies have interrogated inherited variants that may distinguish indolent and aggressive prostate cancer. Several of these studies identified polymorphisms associated with aggressiveness, after adjusting for commonly used clinical variables, and are reviewed in the Table 6.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess prospectively.

Like studies of the genetics of prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes. Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain risk SNPs were also associated with aggressiveness (see table below). There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer. While GWAS designed explicitly for disease aggressiveness have been initiated, most genome-wide analyses to date have relied on datasets previously generated to evaluate prostate cancer risk. The cases from these case-control cohorts were divided into aggressive and nonaggressive subgroups then compared with each other and/or with the control (nonprostate cancer) subjects. Several associations between germline markers and prostate cancer aggressiveness have been reported. However, there remains no accepted set of germline markers that clearly provides prognostic information beyond that provided by more traditional variables at the time of diagnosis.

In independent retrospective series (see Table 6) the prostate cancer risk allele at rs2735839 (G) was associated with less aggressive disease. This risk allele has also been associated with higher PSA levels.[198,238] A hypothesis explaining the association between the nonrisk allele (A) and more aggressive disease is that those carrying the A allele generally have lower PSA levels and are sent for prostate biopsy less often. They subsequently may be diagnosed later in the natural history of the disease, resulting in poorer outcomes.

To definitively identify the inherited variants associated with prostate cancer aggressiveness, GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. Notably, in a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths), no SNP was associated with prostate cancerspecific survival.[239] The authors concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%). As more data regarding rarer variants are generated and validated, the value of inherited variants for therapeutic decision making may be determined.

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2] Prostate cancer in particular has been observed at higher rates in male BRCA2 mutations carriers than in the general population.[3]

The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 7.

Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[6] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[7-9] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.71.1) for the 185delAG mutation, 0.3% (95% confidence interval [CI], 0.20.4) for the 5382insC mutation, and 1.3% (95% CI, 1.01.5) for the BRCA2 6174delT mutation.[10-13] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks (RRs) were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 430) among carriers and 3.8% among noncarriers (95% CI, 3.34.4).[13] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 70 years; 95% CI, 628). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

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Genetics of Prostate Cancer (PDQ)Health Professional ...

Genetics of Skin Cancer (PDQ)Health Professional Version

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocyte cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. Basal keratinocytes lose contact with the basement membrane as they divide. As basal keratinocytes migrate toward the skin surface, they progressively differentiate to form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer."[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can undergo malignant transformation into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are another cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma (reddening of the skin) associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender T-cell responses consisting of increased levels of TH1, TH2, or TH17 cells.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim or can appear somewhat eczematous (see Figure 2 and Figure 3). They often ulcerate (see Figure 2). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI's website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

Enlarge

Figure 2. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

Figure 3. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Enlarge

Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Enlarge

Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer." With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma). (Refer to the PDQ summary on Skin Cancer Prevention for more information about risk factors for skin cancer in the general population.)

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick Type I or II skin were shown to have a twofold increased risk of BCC in a small case-control study.[2] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[3]

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that nonmelanoma skin cancers (NMSCs) have a heritability of 43% (95% confidence interval [CI], 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[4] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[4]

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the mid-60s.[5-10] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[11-14] however, other studies have contradicted this finding.[15-18] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. (Refer to the BCNS section of this summary for more information.) PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[19] Binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[20,21] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[22,23] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[24] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[25] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[26]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[27,28] PTCH2 displays 57% homology to PTCH1.[29] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[27,30]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid BCC syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[31] The syndrome is notable for complete penetrance and high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[26,32] The clinical features of BCNS differ more among families than within families.[33] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[34-36]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[31] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[37] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[38-42] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[43]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[44-47] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[47] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[48,49] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[41,45,50] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[51] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[52]

Other associated benign neoplasms include gastric hamartomatous polyps,[53] congenital pulmonary cysts,[54] cardiac fibromas,[55] meningiomas,[56-58] craniopharyngiomas,[59] fetal rhabdomyomas,[60] leiomyomas,[61] mesenchymomas,[62] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[63-65] In addition, radiation therapy of malignant medulloblastomas in the BCNS population may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[40,41,61]

The diagnostic criteria for BCNS are described in Table 1 below.

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon -like lesions, while larger lesions demonstrate more classic cutaneous features.[66] Nonpigmented BCCs are more common than pigmented lesions.[67] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[45,50] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[67] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[31] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[45,68,69] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[69] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[45,61] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.

Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% CI, 2034), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 3040) (hazard ratio [HR], 1.64; 95% CI, 1.042.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 2837) relative to a median onset of 41 years (95% CI, 3248) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.081.93, P = .014).[70]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[41,45,50,71] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[72,73] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[74] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[41,56] Other reported malignancies include ovarian carcinoma,[75] ovarian fibrosarcoma,[76,77] astrocytoma,[78] melanoma,[79] Hodgkin disease,[80,81] rhabdomyosarcoma,[82] and undifferentiated sinonasal carcinoma.[83]

Odontogenic keratocystsor keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working groupare one of the major features of BCNS.[84] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[37] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[43,85] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[84,86] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[84] A study that analyzed the rate of PTCH1 mutations in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 mutation and an additional 3 individuals had somatic mutations in this gene.[87] Individuals with germline PTCH1 mutations had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[45,88] with higher rates of occurrence in young females.[89]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[50] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[90]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[91,92] fused, splayed or bifid ribs;[93] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[49] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Individuals with PTCH2 mutations may have a milder phenotype of BCNS than those with PTCH1 mutations. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[94]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[95] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline mutations in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[35,36] These mutations were first identified in individuals with childhood medulloblastoma,[96] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU mutations than in those with PTCH1 mutations.[35] SUFU mutations may also be associated with an increased predisposition to meningioma.[58,97] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU mutations for individuals with BCNS who do not have an identifiable PTCH1 mutation.

Rombo syndrome, a very rare probably autosomal dominant genetic disorder associated with BCC, has been outlined in three case series in the literature.[98-100] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[98] Development of BCC occurs in the fourth decade.[98] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[98,100] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[98,99] The genetic basis of Rombo syndrome is not known.

Bazex-Dupr-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[101-103] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[104] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[105]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[101] Documented hair changes with Bazex-Dupr-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[106] a twisted/flattened appearance of the hair shaft on electron microscopy,[107] and increased hair shaft diameter on polarizing light microscopy.[103] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[103] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[108,109]

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[110] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[111] One report cites an incidence of BCC of 44% by age 55 years in this population.[112] Individuals who inherit two EBS mutations may present with a more severe phenotype.[113] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[110] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[114]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for NMSCs recommends complete skin examinations every 6 to 12 months for life.[125]

The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (see Table 4).

Level of evidence: 5

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer.[126] For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii

The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[127] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[127] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[127-129] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with xeroderma pigmentosum, as discussed in the Squamous Cell Carcinoma section of this summary.

A patients cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid courseand for 1 month after completion of isotretinoin and 3 years after completion of acitretinis essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[130] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii

A phase III, double-blind, placebo-controlled clinical trial evaluated the effects of oral nicotinamide (vitamin B3) in 386 individuals with a history of at least two NMSCs within 5 years before study enrollment.[131] After 12 months of treatment, those taking nicotinamide 500 mg twice daily had a 20% reduction in the incidence of new BCCs (95% CI, 6%39%; P = .12). The rate of new NMSCs was 23% lower in the nicotinamide group (95% CI, 438; P =.02) than in the placebo group. No clinically significant differences in adverse events were observed between the two groups, and there was no evidence of benefit after discontinuation of nicotinamide. Of note, this study was not conducted in a population with an identified genetic predisposition to BCC.

Level of evidence (nicotinamide): 1aii

Treatment of individual BCCs in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[132,133] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[45] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[132,133]

Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[134] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.

Level of evidence (imiquimod and photodynamic therapy): 4

Topical treatment with LDE225, a Smoothened agonist, has also been investigated for the treatment of BCC in a small number of patients with BCNS with promising results;[135] however, this medication is not approved in this formulation by the U.S. Food and Drug Administration.

Level of evidence (LDE225): 1

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[136] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[137] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence (vismodegib): 3diii

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer (NMSC), annual incidence estimates range from 1 million to 5.4 million cases in the United States.[1,2]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer.

Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC.[3] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group.[4] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.[5]

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[6] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments.[7] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[8] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.73.8).[9]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation therapy had an increased risk of SCC at the site of previous radiation (OR, 2.94), compared with individuals who had not undergone radiation treatments.[10] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[14]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of NMSCs in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]

Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[23] For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.[24]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk.[28] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[29]

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] A case-control study of 415 cases and 415 controls showed similar findings; relative to Fitzpatrick Type I skin, individuals with increasingly darker skin had decreased risks of skin cancer (ORs, 0.6, 0.3, and 0.1, for Fitzpatrick Types II, III, and IV, respectively).[31] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) The same study found that blue eyes and blond/red hair were also associated with increased risks of SCC, with crude ORs of 1.7 (95% CI, 1.22.3) for blue eyes, 1.5 (95% CI, 1.12.1) for blond hair, and 2.2 (95% CI, 1.53.3) for red hair.

However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline.[30] SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[32,33] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[34] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[34,35] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolins ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[36] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[37]

Immunosuppression also contributes to the formation of NMSCs. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[38-41] NMSCs in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[42,43] Additionally, there is a high risk of second SCCs.[44,45] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[44] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[38,46,47] The risk appears to be highest in geographic areas with high UV exposure.[47] When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[48] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone.[38] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[49]

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[50] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the middle of the sixth decade of life.[26,51-55]

A Swedish study of 224 melanoma index cases and 944 of their first-degree relatives (FDRs) from 154 CDKN2A wild-type families and 11,680 matched controls showed that personal and family histories of melanoma increased the risk of SCC, with relative risks (RRs) of 9.1 (95% CI, 6.013.7) for personal history and 3.4 (95% CI, 2.25.2) for family history.[56]

Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in FDRs. In an independent survey-based study of 415 SCC cases and 415 controls, SCC risk was increased in individuals with a family history of SCC (adjusted OR, 3.4; 95% CI, 1.011.6), even after adjustment for skin type, hair color, and eye color.[31] This risk was elevated to an OR of 5.6 in those with a family history of melanoma (95% CI, 1.619.7), 9.8 in those with a family history of BCC (95% CI, 2.636.8), and 10.5 in those with a family history of multiple types of skin cancer (95% CI, 2.729.6). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[57,58] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[59] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that NMSCs have a heritability of 43% (95% CI, 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[60] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[60]

Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important mutations of the gene as causal. The disorders resulting from single-gene mutations within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine because of the rarity of the genetic mutation.

Identification of a strong environmental risk factorchronic exposure to UV radiationmakes it difficult to apply genetic causation for SCC of the skin. Although the risk of UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of cases of SCC of the skin is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin owing to: (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy, and (2) the relatively low potential for metastasis. Moreover, NMSC is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.

With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.

Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 5 below.

Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that NMSC was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times what would be expected in the general population.[61]

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Review of the Status of Aquaculture Genetics

Lakhaanantakun, A. 1992. The effects of triploidy on survival rate, growth rate and feed conversation ratio of walking catfish (Clarias macrocephalus Gunther). M.Sc. Thesis, Kasetsart University, Bangkok, 74 pp.

LaPatra, S.E., Lauda, K.A., Jones, G.R., Shewmaker, W.D., Groff, J.M. & Routledoe, D. 1996. Susceptibility and humoral response of brown trout x lake trout hybrids to infectious hematopoietic necrosis virus: a model for examining disease resistance mechanisms. Aquaculture, 146: 179-188.

LaPatra, S.E., Parsons, J.E., Jones, G.R. & McRoberts, W.O. 1993. Early life stage survival and susceptibility of brook trout, coho salmon, and rainbow trout x brook trout or coho salmon hybrids to IHN. J. Aquat. Anim. Health, 5: 270-264.

Lee, W.J. & Kocher, T.D. 1996. Microsatellite DNA markers for genetic mapping in Oreochromis niloticus. J. Fish Biol. 49: 169-171. Leeprasert, K. 1987. Genetic parameters of some quantitative traits in Pangasius sutchi Fowler. M.Sc. Thesis, Kasetsart University, Bangkok, 75 pp.

Lester, L.J., Lawson, K.S., Abella, T.A. & Palada, M.S. 1989. Estimated heritability of sex ratio and sexual dimorphism in tilapia. Aquacult. Fish. Manage. 20: 369-380.

Li, Y, Wilson, K.J., Byrne, K., Whan, V., Iglesis, D., Lehnert, S.A., Swan, J., Ballment, B., Fayazi, Z., Kenway, M., Benzie, J., Pongsomboon, S., Tassanakajon, A. & Moore, S.S. 2000. International collaboration on genetic maping of the black tiger shrimp, Penaeus monodon: progress update. Plant and Animal Genome VIII, p. 8. San Diego, January 9-12, 2000.

Lim, C., Leamaster, B. & Brock, J.A. 1993. Riboflavin requirement of fingerling red hybrid tilapia grown in seawater. J. World Aquacult. Soc. 24: 451-458.

Linhart, O., Flajshans, M., Gela, D., Duda, P., Slechta, V. & Slechtova, V. 1998. Breeding programme of common carp in the Czech Republic. XVIII-th Genetic Days, Ceske Budejovice.

Liu, Q., Goudi, C.A., Simco, B.A., Davis, K.B. & Morizot, D.C. 1992. Gene-centromere mapping of six enzyme loci in aynogenctic channel catfish. J. Hered. 83: 245-248.

Liu, Z.J. & Dunham, R.A. 1998. Genetic linkage and QTL mapping of ictalurid catfish. Alabama Agricultural Experiment Station Circ. Bull. 321: 1-19.

Liu, Z.J., Li, P., Argue, B. & Dunham, R.A.1998a. Inheritance of RAPD markers in channel catfish (Ictalurus punctatus), blue catfish (I. furcatus) and their Fl, F2 and backcross hybrids. Anim. Genet. 29: 58-62.

Liu, Z.J., Nichols, A., Li, P. & Dunham, R.A. 1998b. Inheritance and usefulness of AFLP markers in channel catfish (Ictalurus punctatus), blue catfish (I. furcatus) and their Fl, F2 and backcross hybrids. Mol. Gen. Genet. 258: 260-268.

Liu, Z.J., Li, P., Argue, B.P. & Dunham, R.A. 1999a. Random amplified polymorphic DNA markers: usefulness for gene mapping and analysis of genetic variation of catfish. Aquaculture, 174: 59-68.

Liu, Z.J., Li, P., Kucuktas, H., Nichols, A., Tan, G., Zheng, X., Argue, B.J., Yant, R. & Dunham, R.A. 1999b. Development of AFLP markers for genetic linkage mapping analysis using channel catfish and blue catfish interspecific hybrids. Trans. Am. Fish. Soc. 128: 317-327.

Liu, Z.J., Tan, G., Kucuktas, H., Li, P., Karsi, A., Yant, D.R. & Dunham, R.A. 1999c. High levels of conservation at microsatellite loci among ictalurid catfishes. J. Hered. 90: 307-312.

Liu, Z.J., Tan, G., Li, P. & Dunham, R.A. 1999d. Transcribed dinucleotide microsatellites and their associated genes from channel catfish, Ictalurus punctatus. Biochem. Biophys. Res. Comm. 259: 190-194.

Liu, Z.J., Karsi, A. & Dunham, R.A. (in press) Development of polymorphic EST markers suitable for genetic linkage mapping of catfish. Mar. Biotechnol.

Macaranas, J.M., Taniguchi, N., Pante, M.J.R., Capili, J.B. & Pullin, R.S.V. 1986. Electrophoretic evidence for extensive hybrid gene introgression into commercial Oreochromis niloticus (L.) stocks in the Philippines. Aquacult. Fish. Manage. 17: 249-258.

Mahapatra, K.D., Meher, P.K., Saha, J.N., Gjerde, B., Reddy, P.V.G.K., Jana, R.K., Sahoo, M. & Rye, M. 2000. Selection response of rohu, Labeo rohita, for two generations of selective breeding. The Fifth Indian Fisheries Forum, 17-20 January, 2000, Abstracts.

Mair, G.C., Abucay, J.S., Beardmore, J.A. & Skibinski, D.O.F. 1995. Growth performance trials of genetically male tilapia (GMT) derived from YY males in Oreochromis niloticus L.: on-station comparisons with mixed sex and sex reversed male populations. Aquaculture, 137: 313-322.

Mair, G.C., Scott, A.G., Penman, D.J., Skibinski, D.O.F. & Beardmore, J.A. 1991. Sex determination in Oreochromis. I. Gynogenesis, triploidy and sex reversal in Oreochromis niloticus. Theor. Appl. Genet. 82: 144-152.

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Review of the Status of Aquaculture Genetics

BEHAVIORAL GENETICS: THE SCIENCE OF … – PubMed Central (PMC)

1. See generally Plomin Robert, et al. Behavioral Genetics. 4th ed. 72-92. 2001. (reviewing basic structure of adoption and twin designs); Baker Laura A. Methods for Understanding Genetic and Environmental Influences in Normal and Abnormal Personality. In: Strack S, editor. Differentiating Normal and Abnormal Personality. 2006. (in press) (reviewing the major classical genetic designs as well as their assumptions, strengths, and weaknesses).

2. Genes do not always act in a dominant or recessive fashion (such that one gene masks the effects of another gene). Instead, each gene at a given locus may contribute additively to the phenotype. Even when dominant genes are involved, however, additive effects can appear.

3. Quantitative traits are those that exist on a continuum, such as height, weight, extraversion, or general intelligence; qualitative traits are usually all or nothing phenomena such as disease status, eye color, criminal convictions. The term complex is often used synonymously with quantitative.

4. See generally Sham Pak. Recent Developments in Quantitative Trait Loci Analysis. In: Plomin Robert, et al., editors. Behavioral Genetics IN THE Postgenomic Era. Vol. 41 2003.

5. Id.

6. An allele is a variation of a particular gene at a given locus. Genotype refers to the combination of alleles at a given locus, or more generally to a combination of alleles at two or more loci.

7. See infra Part IV.B.

9. Id.

10. Id.

11. Id.

12. Id.

13. For example, official criminal records represent clear violations of legal norms, but they may be incomplete to the extent that undetected crimes may exist. Self-reported antisocial behavior may be used to assess a broader range of behaviors, including both detected and undetected criminal activity as well as less serious, noncriminal antisocial behavior, but such self-reports will be influenced by the respondent's dishonesty. Parental ratings of antisocial behavior in young children reflect perhaps the most intimate knowledge of the children's behavior (apart from that of the children themselves); however, parents may be unable to judge the child's motivations (such as whether aggressive behavior may be proactive or the result of provocation), and parents have limited observations of the child's behavior outside of the home. Teacher reports provide useful information about school-related behaviors, but these may also lack information about the child's motivations and may not adequately distinguish between victims and perpetrators during conflicts among children.

14. See Rhee & Waldman, supra note 8, at 515.

15. Id. at 514.

16. Id.

17. Id.

18. Id.

19. Id. at 512-14.

20. Id. at 512-13.

21. Id. at 512-14.

22. Id. at 495.

23. Baker Laura A., et al. Genetic and Environmental Bases of Antisocial Behavior in Children. unpublished manuscript, on file with Law and Contemporary Problems.

24. Id.

25. Id.

26. Id.

27. Id. Compare Rhee & Waldman, supra note 8, at 516-17, 522.

28. See, e.g., Rhee & Waldman, supra note 8.

29. Id.

31. See, e.g. , Dilalla Lisabeth Fisher, Gottesman Irving I. Heterogeneity of Causes for Delinquency and Criminality: Lifespan Perspectives. 1 Dev. & Psychopathology. 1990;339

32. Rhee & Waldman, supra note 8, at 494.

37. See, e.g ., Torgersen S, et al. The Psychometric-Genetic Structure of DSM-III-R Personality Disorder Criteria. 7 J. Personality Disorders. 1993;196

38. See Cloninger CR, Gottesman II. Genetic and Environmental Factors in Antisocial Behavior Disorders. In: Mednick SA, et al., editors. The Causes of Crime: New Biological Approaches. Vol. 92. 1987. pp. 96100.

40. Hutchins & Mednick, supra note 36.

41. Wilson James Q., Herrnstein Richard J. Crime and Human Nature. 1985:10412.;cf. Hyde Janet S. How Large Are Gender Differences in Aggression? A Developmental Analysis. 20 Developmental Psychol. 1984;722 (discussing gender variation in aggression).

42. See Rhee & Waldman, supra note 8, at 494 (noting that genetic effects on antisocial behavior are equal between the sexes, but that genetic effects on aggression are not equal).

43. See Cloninger & Gottesman, supra note 38.

44. Rhee & Waldman, supra note 8.

45. Cloninger & Gottesman, supra note 38.

46. Baker et al., supra note 23.

47. Baker Laura A., Raine Adrian. The Delinquency Interview for Children (DI-C): A Self-report Measure of Antisocial Behavior. 2005 unpublished manuscript, on file with Law and Contemporary Problems.

48. Id.

49. Id.

50. Raine Adrian, et al. Biological Risk Factors for Antisocial and Criminal Behavior. In: Raine Adrian., editor. Crime and schizophrenia: Causes and Cures. forthcoming.

51. Baker & Raine, supra note 47.

52. Rhee & Waldman, supra note 8.

53. Baker & Raine, supra note 47.

54. See infra Part V.A.

60. Robert Cloninger C, et al. Epidemiology and Axis I Comorbidity of Antisocial Personality. In: Stoff David M., et al., editors. Handbook of Antisocial Behavior. Vol. 12 1997.

61. Robins Lee N. Deviant Children Grown Up: A Sociological and Psychiatric Study of Sociopathic Personality. 1966

62. See Robins Lee N., et al. Antisocial Personality. In: Robins Lee N., Regier Darrel A., editors. Psychiatric Disorders in America: The Epidemilogic Catchment Area Study. Vol. 258. 1991. p. 264. (describing the common remission of the disorder as the individual advances into adulthood).

63. Id. at 25960.

64. Id. at 260.

65. Id.

66. van den Bree Marian B.M., et al. Antisocial Personality and Drug Use DisordersAre They Genetically Related? In: Fishbein Diane H., editor. The Science, Treatment, and Prevention of Antisocial Behaviors: Application to the Criminal Justice System. 8-1. 2000. pp. 8-18-2.

67. Robins et al, supra note 62, at 271.

68. Cloninger & Gottesman, supra note 38.

69. Van den Bree et al., supra note 66, at 8-6.

70. Id.

72. American Psychological Ass'n . Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Vol. 85. 1994.

74. Id.

76. Robins, supra note 61, at 141-42.

79. See Robins, supra note 61, at 163-66.

80. See, e.g., Lahey & Loeber, supra note 77.

81. Scourfield et al., supra note 71, at 489.

83. Gelhorn et al., supra note 73, at 588. Thapar et al., supra note 82, at 226. Cadoret et al., supra note 34.

84. Scourfield et al., supra note 71, at 494. Eaves et al., supra note 57, at 973.

86. Id.

87. Id., at 352.

88. Coolidge et al., supra note 82, at 282 tbl.4 (finding a heritability estimate of 0.61); Eaves et al., supra note 57, at 974 tbl.3 (finding heritability of fourteen percent for girls as measured by their fathers' responses to questionnaires and heritability of sixty-five percent for boys as measured from interviews with their fathers).

89. Goldman David, Fishbein Diana H. Genetic Bases for Impulsive and Antisocial Behaviors Can Their Course Be Altered? The Science, Treatment, and Prevention of Antisocial Behaviors: Application to the Criminal Justice System , supra note 70, at 9-1, 9-2.

91. Goldman & Fishbein, supra note 89, at 9-6.

94. Coccarro et al., supra note 90 at 234-35.

95. Goldman & Fishbein, supra note 89, at 9-6.

96. Coccarro et al., supra note 90 at 234-35.

98. Goldman & Fishbein, supra note 89, at 9-2.

100. Thapar et al., supra note 99 at 105.

102. See Lahey Benjamin, Loeber Rolf. Handbook of Antisocial Behavior. Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Adult Antisocial Behavior: A Life Span Perspective. supra note 60, at 51.

105. Thapar et al., supra note 99, at 109; Barkley, supra note 99.

106. Barkley Russell A. ADHD and the Nature of Self-Control. 1997:3741.

107. Thapar et al., supra note 99, at 106-09. Indeed, first-degree relatives of male probands were five times more likely to be diagnosed with ADHD than relatives of the normal controls.

110. Thapar et al., supra note 99, at 107.

113. See, e.g., Levy et al., supra note 109. Sherman et al., supra note 109. Silberg et al., supra note 111.

115. Barkley, supra note 99, at 4041.

118. Coolidge et al., supra note 82.

120. See id. at 58-65.

122. Coolidge et al., supra note 117.

123. Id.

124. See Raine Adrian. The Psychopathology of Crime: Criminal Behavior as Clinical Disorder. 1993:21516.

125. Coolidge et al., supra note 82, at 275. See generally American Psychological Ass'n, supra note 72.

126. Coolidge et al., supra note 82, at 275.

127. Id.

128. Alcohol use is presumed to contribute to violence because of the pharmacological properties of the drug, as well as expectancies and societal norms surrounding these aspects. See generally White Helene Raskin. Alcohol, Illicit Drugs, and Violence. Handbook of Antisocial Behavior , supra note 60, at 511.

129. White, supra note 128.

130. Id. at 512.

132. Id.

135. Hicks et al., supra note 131, at 923. Kendler et al., supra note 134. Krueger et al., supra note 134. Jacobson et al., supra note 134.

136. See, e.g., Hicks et al., supra note 131, at 923. Kendler et al., supra note 134, at 92930. Krueger et al., supra note 134, at 41113. Jacobson et al., supra note 134.

137. See, e.g., Hicks et al., supra note 131, at 923.

138. Id. at 92427.

141. Falconer DS, Mackay Trudy F.C. Introduction to Quantitative Genetics. 4th ed. 1996. pp. 31213.

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BEHAVIORAL GENETICS: THE SCIENCE OF ... - PubMed Central (PMC)

Genetics of human male infertility.

Infertility is defined as a failure to conceive in a couple trying to reproduce for a period of two years without conception. Approximately 15 percent of couples are infertile, and among these couples, male factor infertility accounts for approximately 50 percent of causes. Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In more than half of infertile men, the cause of their infertility is unknown (idiopathic) and could be congenital or acquired. Infertility in men can be diagnosed initially by semen analysis. Seminograms of infertile men may reveal many abnormal conditions, which include azoospermia, oligozoospermia, teratozoospermia, asthenozoospermia, necrospermia and pyospermia. The current estimate is that about 30 percent of men seeking help at the infertility clinic are found to have oligozoospermia or azoospermia of unknown aetiology. Therefore, there is a need to find the cause of infertility. The causes are known in less than half of these cases, out of which genetic or inherited disease and specific abnormalities in the Y chromosome are major factors. About 10-20 percent of males presenting without sperm in the ejaculate carry a deletion of the Y chromosome. This deleted region includes the Azoospermia Factor (AZF) locus, located in the Yq11, which is divided into four recurrently deleted non-overlapping subregions designated as AZFa, AZFb, AZFc and AZFd. Each of these regions may be associated with a particular testicular histology, and several candidate genes have been found within these regions. The Deleted in Azoospermia (DAZ) gene family is reported to be the most frequently deleted AZF candidate gene and is located in the AZFc region. Recently, a partial, novel Y chromosome 1.6-Mb deletion, designated "gr/gr" deletion, has been described specifically in infertile men with varying degrees of spermatogenic failure. The DAZ gene has an autosomal homologue, DAZL (DAZ-Like), on the short arm of the chromosome 3 (3p24) and it is possible that a defective autosomal DAZL may be responsible for the spermatogenic defect. The genetic complexity of the AZF locus on the long arm of the Y chromosome could be revealed only with the development of sequence tagged sites. Random attacks on the naked mitochondrial DNA (mtDNA) of sperm by reactive oxygen species or free radicals will inevitably cause oxidative damage or mutation to the mitochondrial genome with pathological consequences and lead to infertility in males. The key nuclear enzyme involved in the elongation and repair of mtDNA strands is DNA polymerase gamma, mapped to the long arm of chromosome 15 (15q25), and includes a CAG repeat region. Its mutation affects the adenosine triphosphate production. The introduction of molecular techniques has provided great insight into the genetics of infertility. Yet, our understanding of the genetic causes of male infertility remains limited.

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Genetics of human male infertility.

Definitions for Terms in Genetics Problems

Definitions for terms in genetics problems

All the different forms of the same gene.

All genes on chromosomes other than the sex chromosomes (X and Y).

One strand of a replicated chromosome as illustrated in the image of a chromosome at the right. A single strand by itself with it's own centromere is a chromosome and not a chromatid.

A single (before replication) or double (after replication) strand of DNA with only a single centromere. Chromosomes contain the loci for alleles of different genes. The illustration below shows a chromosome with the parts labeled before (on the left) and after (on the right) replication.

A process that occurs during prophase I of meiosis in which genetic material from the chromatid of one chromosome exchanges places with the material from the same area of a chromatid on it's homolog. This process increases the variation in gametes produced by an individual. The images below illustrate a homologous pair of chromosomes before (on the left) and after (on the right) crossing over has occurred.

Cells which have two copies of a gene, on a pair of homologous chromosomes.

An allele which, if present, masks the effect of any recessive allele paired with it. Indicated by a capital letter.

first-generation offspring (children).

second-generation offspring (grand children).

The haploid cells produced by meiosis which later fuse to form the diploid zygote. In humans, these are the eggs and sperm.

Units of information about specific traits, passed from parents to offspring. Each gene has a specific location (locus) on a chromosome and may come in several forms (alleles).

The actual genes for a trait present in an individual.

The expected numbers of different genotypes produced by a particular cross. Example: 1 RR, 2 Rr, and 1 rr individuals could result from a cross of two Rr individuals. The genotypic ration is 1:2:1.

Cells which have only one allele from the originally homologous pair. In humans, gametes are the only haploid cells.

The two alleles of a pair are not identical (for example: one dominant and one recessive allele for the color trait in roses).

A pair of chromosomes in the same individual that carry the same type of information (eye color) but not necessarily the same alleles (blue or brown). One of these "homologs" comes from the individual's mother and one from the father.

Both alleles of a gene in a homologous pair are identical.

Genes that appear on the same chromosome and that do not sort independently during meiosis.

The physical location of the alleles of a gene on it's chromosome (See the definition for chromosome for an image).

A type of cell division that produces haploid gametes. The image below shows the very basic steps of meiosis and it's products.

A change in a gene's molecular structure and thus it's information about a trait.

parental generation

An individual's observable traits (how the organism looks, behaves, etc.).

The expected numbers of different phenotypes produced by a particular cross. Example: 3 red flowered plants and 1 white flowered plant result from a cross of two red flowered plants. The phenotypic ratio is 3:1.

A graphical representation of a cross between two individuals and the possible genotypes of the offspring produced. The gametes of one individual are placed across the top of the square and the gametes of the other individual are placed down the left side. The gametes are then combined in the cells of the square. Below is an example of a dihybrid cross between two individuals worked in the punnett square.

An allele which must be homozygous for it's effect to be observed. Indicated by a lowercase letter.

sex-linked genes are those that are carried on the X chromosome. In humans, females carry 2 X chromosomes while males carry only one.

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Definitions for Terms in Genetics Problems

Scientist Explains the Genetics of Male Pattern Baldness

If youre new to Quora, the question and answer website that rapidly seems to have trumpedYahoo Answers, youll be thrilled to hear its all brilliantly simple. People post a question that theyd like an answer to, and anyone from random people with an opinion to world-famous experts can post a reply, with the best answers quickly up-voted. While there are plenty of queries about Beyonc, NASA and conspiracy theories, there are also some interesting entries about hair loss, too.

One of the best threads is based around the question What are the genetics of Male Pattern Baldness? While it might only have garnered just two replies to date, one of these has attracted more than 4,000 views. And the fact that the answer comes from Adriana Heguy, who says she has worked in genetics and genomics for the past two decades probably helps.

The first thing that Ms Heguy does is caution how complex the science behindall this is. She also admits that the genetics of Androgenetic Alopecia (genetic baldness) is not really well understood. Acknowledging that genetic baldness is a highly heritable condition, so is most likely to be passed on through families, she does go on to explain that there is furtherevidence that non-genetic factors also play a part. Although she does not elaborate on these, this is likely a reference to issues which can exacerbate or trigger hair loss, such asstress, illness ordietary imbalances.

Of the specific genes thought to play a part in Male Pattern Baldness, Ms Heguy first mentions the androgen receptor (AR) gene. She points out that because this receptor is on the X chromosome which is inherited from your mother the myth persists that men need only look at the maternal line of their family tree to see if theyre likely to go bald or not.

But it (AR) is not the only gene involved, Ms Heguy explains, or even the main gene. There are genes in basically all chromosomes that have been implicated in Androgenetic Alopecia, and this is what makes it so difficult to unravel.

This fits researchers findings that it is, in fact, more likely any actively expressed genetic traits are likely to come from our fathers side of the family including hair loss. People are able to carry the genes for androgenetic alopeciawithout displaying any of the signs if these genes lie dormant and are not active, which can explain why sometimes hair loss appears to skip a generation.

Androgen receptors are also known as NR3C4 which stands for Nuclear Receptor subfamily 3, group C, member 4 and they control cell behaviour. When testosterone reacts with the enzyme5-alpha-reductase in a cell, it is converted into the androgen dihydrotestone (DHT) and, asthose with an inherited predisposition to male pattern baldness have an innate sensitivity to DHT,the hair miniaturisation process starts.

Male Pattern Baldness begins when the DHTgradually impedes hairgrowth by binding to the androgen receptors in the hair follicle and causing increasingly thinning hair, theneventually stops them from producing hair altogether. For this reason, successful treatment of Male Pattern Baldness ofteninvolves the use of a clinically-proven drug, finasteride 1mg,which inhibits the production of DHT.

A second product, and one that Belgravia hair loss specialists often recommend, particularly for stubborn areas such as a receding hairline, is the topical daily treatmenthigh strength minoxidil. When applied directly to the affected areas of the scalp as advised, thiscan encourage accelerated hair growth. This is most often used by Belgravias male clients as part of a comprehensive treatment course alongside finasteride and hair growth boosters to maximise the chances of seeing an improvement to both their hair loss and the condition of their hair.

While Ms Heguy admits that we are still far from a definitive cure forAndrogenetic Alopecia by which she presumably means a single-dose, one-off medication that will completely stop MPB before it has even started she does offer some hope to men who have already lost their hair to the condition: If there is any consolation for men distressed about hair loss, if it was a phenotype that was repulsive to females, the gene variants would have been weeded out a long time ago, by sexual selection. Many of us find bald heads very manly and attractive.

The Belgravia Centre is the leader in hair loss treatment in the UK, with two clinics based in Central London.If you are worried about hair loss you canarrange afree consultationwith a hair loss expert or complete ourOnline Consultation Formfrom anywhere in the UK or the rest of the world. View ourHair Loss Success Stories, which are the largest collection of such success stories in the world and demonstrate the levels of success that so many of Belgravias patients achieve. You can also phone020 7730 6666any time for our hair loss helpline or to arrange a free consultation.

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Scientist Explains the Genetics of Male Pattern Baldness

Male Infertility – Genetics & IVF Institute

Among infertile couples, either partner may contribute to the failure to conceive. It is estimated that 30-40% of infertility is due to male abnormalities, another 20% to a combination of various factors, and about 30-40% to problems with the female partner.

The Genetics & IVF Institute offers expert diagnosis and treatment of male infertility. Our male infertility treatment offers the following benefits:

If donor sperm is needed, our on-site sperm bank, Fairfax Cryobank, provides a large selection of high quality, fully screened donor sperm. In fact, GIVF patients who choose donor sperm from Fairfax Cryobank can enjoy free shipping and handling, as well as same day delivery. Click here to learn more about Fairfax Cryobank.

An important component in the treatment of men with infertility is establishing the correct diagnosis. Our medical specialists conduct a thorough clinical evaluation of each couple. State of the art semen analysis and specialized sperm function testing are available, including measurement of sperm capacitation and acrosome reaction, computer assisted sperm motion analysis (CASA), sperm antibody, and leukocyte quantitation. An appropriate individualized treatment is then recommended.

Intracytoplasmic sperm injection (ICSI), is the direct injection of sperm into eggs obtained for in vitro fertilization (IVF). GIVF has extensive experience with ICSI and have established thousands of pregnancies using this technique. ICSI frequently permits the establishment of pregnancy in even the most difficult types of male infertility, including men who have fewer than 100 sperm in their semen. For men with no sperm at all in their semen, sperm can be obtained directly from the testis with non-surgical sperm aspiration (NSA). Testicular sperm can fertilize when injected directly into eggs using ICSI.

The ICSI Process:

ICSI has been widely used for over ten years. GIVF performed the first ICSI pregnancy in the US and since then the procedure has become the standard of care for male factor infertility. The American Society for Reproductive Medicine (ASRM) considers it a safe, effective procedure that has helped thousands of men becomes fathers. If you have questions or concerns about ICSI, please let your doctor or nurse know so that we can discuss it with you.

The difference between IVF and ICSI is in how the sperm meets the egg. With traditional IVF, the sperm is poured on the egg. That is to say that the sperm is put into the petri dish that the eggs are in and fertilization takes place in the dish the same way it would in the fallopian tubes. Millions of sperm compete to fertilize each egg.

With ICSI, an individual sperm is injected into a single egg. ICSI is used when there is a problem with the sperm; thereby the likelihood of fertilization is increased if we inject the sperm directly into the egg. ICSI does not guarantee that fertilization takes place, but it does ensure that sperm meets egg. With traditional IVF, the sperm may never pass through the outer zona of the egg. Your doctor will advise you if ICSI is recommended for you based on the results of the semen testing and a few other risk factors.

Non-surgical sperm aspiration (NSA) is a quick and painless procedure performed in our clinic under sedation. A tiny needle is used to extract sperm directly from the testis. While the ejaculate normally contains 100 million to 300 million sperm, aspiration of as few as 100-200 sperm by NSA have been enough to achieve pregnancy when it is combined with ICSI.

NSA may be recommended for men who:

It is possible to reverse a vasectomy by having bypass surgery, but the operation is frequently unsuccessful, especially for men with long-standing vasectomies. Additionally, sperm quality after vasectomy reversal is often reduced and ICSI is required even if sperm appear in the ejaculate. For many men, NSA eliminates the need for vasectomy reversal surgery.

Prior to the development of NSA, men with no sperm in their ejaculate had to undergo surgery to remove sperm either from their testes or from tubes connected to the testis. The operation required a costly hospital stay and a lengthy recuperation. NSA is a quick and painless procedure performed at GIVF, does not require hospitalization, and recovery is virtually immediate. It should be noted that for some men, a single NSA procedure may yield enough sperm to permit sperm freezing for several subsequent ICSI attempts.

NSA must be done with ICSI because testicular sperm cannot enter eggs by themselves. In order to accomplish this, the female partner receives a series of medications to increase the number of eggs created by the ovary as in a conventional IVF cycle. When the eggs grow to adequate size, they are extracted non-surgically at GIVF under sedation, and NSA is scheduled the same day. After egg retrieval and sperm aspiration, our embryologists inject each egg with a single sperm. Two days after the procedures, definite information regarding fertilization of the eggs, and the number of embryos are available. Embryos are transferred back to the uterus two or three days following fertilization; additional embryos may be cryopreserved (frozen), as requested.

If donor sperm is needed, our on-site sperm bank, Fairfax Cryobank, provides a large selection of high quality, fully screened donor sperm. In fact, GIVF patients who choose donor sperm from Fairfax Cryobank can enjoy free shipping and handling, as well as same day delivery. Click here to learn more about Fairfax Cryobank.

Click here or call 800.552.4363 or 703.698.7355 to schedule a fertility consultation at GIVF.

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Male Infertility - Genetics & IVF Institute

The Genetics of Balding | Understanding Genetics

Finding a gene can be like a treasure hunt.

At first it might seem weird that researchers found a bit of DNA involved in baldness but that they can't figure out why it is involved. The reason for this has to do with the way people find DNA involved in disease.

Human DNA is a long string of 3 billion letters (or bases). Each human is unique because these letters are arranged in a certain order*.

It is too expensive to figure out all of the bases of the DNA from the hundreds or thousands of people involved in a typical study. So what scientists have done is figured out millions of places in human DNA where these letters are often different between people. (This is called the HapMap.)

These differences or SNPs (single nucleotide polymorphisms) work like landmarks to help scientists find which part of the DNA to focus on. They are like clues on a treasure map.

The first part in using a treasure map is narrowing down what part of the world the treasure is in. Imagine the map shows that the treasure is in San Francisco. Then there might be clues that the treasure is near a certain hill or near an oddly shaped tree. Perhaps the treasure is buried near the tower on Mt. Sutro.

With this information, the treasure seekers can get digging. If they know a treasure is in San Francisco, they can't just dig up the whole city. But if they know it is near the tower on Mt. Sutro, then they can dig all over that area.

This is how DNA searches work too. Scientists use SNPs as landmarks to narrow down DNA regions to focus on.

Instead of a treasure map, scientists use the HapMap. They use this map to compare the DNA of people with and without the condition they are interested in. In these studies, scientists compared the DNA of balding and not balding men.

The first study looked at German men. One experiment in this study compared 296 balding men to 347 German men and women who were not seriously bald. The researchers looked at over 500,000 different spots on their DNA and found that bald people shared a number of landmarks in a 1.7 million base chunk of chromosome 20. They had narrowed it down to San Francisco.

More clues led them to a single letter difference that was shared by many of the balding men. A second experiment looked at 319 bald men and compared them to 234 men who weren't bald by the age of 60. This second experiment confirmed the results of the first one.

The second study was done similarly. They compared 578 Swiss men with male pattern baldness to 547 Swiss men who weren't balding. They found a different SNP near the one the first study found. They confirmed that this DNA difference as associated with baldness in over 3000 other individuals from a variety of Northern European countries.

So these two studies have narrowed down where the "treasure" is. They made it to Mt. Sutro. They know that something on a small section of chromosome 20 is partly responsible for balding in Northern European men.

The next steps will be to do some serious digging and to find the treasure. In other words, the researchers need to figure out what in this region is causing these men to bald early. And once they do that, they need to find out why these men go bald. With that information, they might be able to create medicines that can treat baldness.

Usually there is a gene nearby that researchers can investigate. In this case, there isn't. The SNPs are in the middle of nowhere with the nearest gene being at least 350,000 bases away. So researchers have their work cut out for them.

In doing these studies, the researchers also rediscovered the DNA difference that men can inherit from their mom's dad that can lead to early balding.

*The exception is identical twins who have essentially the same DNA but are still unique for environmental reasons.

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The Genetics of Balding | Understanding Genetics

Genetics / Does the male or female carrier the gene for twins.

Expert: Kristiann Dougherty, PhD - 9/22/2007

I can answer questions related to Mendelian inheritance, heredity, population genetics, genetic diseases, molecular biology techniques, transcription/translation, mitosis, meiosis. Please don't ask for predictions about what (or whom) your unborn baby will look like. I can't see the future, and in most cases, I am unable to provide a satisfactory answer, just a range of possiblities. That being said, I will attempt to answer questions related to children already born.

Conducted research in the field for about 12 years. Also am a Biology professor so I teach most of these subjects on a regular basis. Familiar with many examples to use as illustations.

Organizations Natl Association of Biology Teachers

Publications Journal Biological Chemistry Proceedings of the National Academy of Science (PNAS) Cancer Research

Education/Credentials BS in Biology, with concentration in Genetics - Purdue University PhD in Molecular Biology and Human Genetics - Johns Hopkins University

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Genetics / Does the male or female carrier the gene for twins.

Genetics – NHS Choices

Introduction

Genetics is the branch of science that deals with how you inherit physical and behavioural characteristics including medical conditions.

Your genes are a set of instructions for the growth and development of every cell in your body. For example, they determine characteristics such as your blood group and the colour of your eyes and hair.

However, many characteristics aren't due to genes alone environment also plays an important role. For example, children may inherit 'tall genes' from their parents, but if their diet doesn't provide them with the necessary nutrients, they may not grow very tall.

Genes are packaged in bundles called chromosomes. In humans, each cell in the body contains 23 pairs of chromosomes 46 in total.

You inherit one of each pair of chromosomes from your mother and one from your father. This means there are two copies of every gene in each cell, with the exception of the sex chromosomes, X and Y.

The X and Y chromosomes determine the biological sex of a baby. Babies with a Y chromosome (XY) will be male, whereas those without a Y chromosome will be female (XX). This means that males only have one copy of each X chromosome gene, rather than two, and they have a few genes found only on the Y chromosome and play an important role in male development.

Occasionally, individuals inherit more than one sex chromosome. Females with three X chromosomes (XXX) and males with an extra Y (XYY) are normal, and most never know they have an extra chromosome. However, females with one X have a condition known as Turner syndrome, and males with an extra X have Klinefelter syndrome.

The whole set of genes is known as the genome. Humans have about 21,000 genes on their 23 chromosomes, so the human genome contains two copies of those 21,000 (except for those on X and Y in males).

Deoxyribonucleic acid (DNA) is the long molecule found inside chromosomes that stores genetic information. It is tightly coiled into a double helix shape, which looks like a twisted ladder.

Each 'rung' of the ladder is made up of a combination of four chemicals adenine, thymine, cytosine and guanine which are represented as the letters A, T, C and G.

These 'letters' are ordered in particular sequences within your genes and they contain the instructions to make a particular protein, in a particular cell, at a particular time. Proteins are complex chemicals that are the building blocks of the body. For example, keratin is the protein in hair and nails, while haemoglobin is the red protein in blood.

There arearound six billion letters of DNA code within each cell.

As well as determining characteristics such as eye and hair colour, your genes can also directly cause or increase your risk of a wide range of medical conditions.

Although not always the case, many of these conditions occur when a child inherits a specific altered (mutated) version of a particular gene from one or both of their parents.

Examples of conditions directly caused by genetic mutations include:

There are also many conditions that are not directly caused by genetic mutations, but can occur as the result of a combination of an inherited genetic susceptibility and environmental factors, such as a poor diet, smoking and a lack of exercise.

Read more about how genes are inherited.

Genetic testing can be used to find out whether you are carrying a particular genetic mutation that causes a medical condition.

This can be useful for a number of purposes, including diagnosing certain genetic conditions, predicting your likelihood of developing a certain condition and determining if any children you have are at risk of developing an inherited condition.

Testing usually involves taking a blood or tissue sample and analysing the DNA in your cells.

Genetic testing can also be carried to find out if a foetus is likely to be born with a certain genetic condition by extracting and testing a sample of cells from the womb.

Read more about genetic testing and counselling.

The Human Genome Project is an international scientific project that involves thousands of scientists around the world.

The initial project ran from 1990 to 2003. Its objective was to map the immense amount of genetic information found in every human cell.

As well as identifying specific human genes, the Human Genome Project has enabled scientists to gain a better understanding of how certain traits and characteristics are passed on from parents to children.

It has also led to a better understanding of the role of genetics in a number of genetic and inherited conditions.

Page last reviewed: 08/08/2014

Next review due: 08/08/2016

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Genetics - NHS Choices

Y chromosome – Genetics Home Reference

Reviewed January 2010

The Y chromosome is one of the two sex chromosomes in humans (the other is the X chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The Y chromosome spans more than 59 million building blocks of DNA (base pairs) and represents almost 2 percent of the total DNA in cells.

Each person normally has one pair of sex chromosomes in each cell. The Y chromosome is present in males, who have one X and one Y chromosome, while females have two X chromosomes.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. The Y chromosome likely contains 50 to 60 genes that provide instructions for making proteins. Because only males have the Y chromosome, the genes on this chromosome tend to be involved in male sex determination and development. Sex is determined by the SRY gene, which is responsible for the development of a fetus into a male. Other genes on the Y chromosome are important for male fertility.

Many genes are unique to the Y chromosome, but genes in areas known as pseudoautosomal regions are present on both sex chromosomes. As a result, men and women each have two functional copies of these genes. Many genes in the pseudoautosomal regions are essential for normal development.

Genes on the Y chromosome are among the estimated 20,000 to 25,000 total genes in the human genome.

Many genetic conditions are related to changes in particular genes on the Y chromosome. This list of disorders associated with genes on the Y chromosome provides links to additional information.

Changes in the structure or number of copies of a chromosome can also cause problems with health and development. The following chromosomal conditions are associated with such changes in the Y chromosome.

In most individuals with 46,XX testicular disorder of sex development, the condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. The translocation affects the gene responsible for development of a fetus into a male (the SRY gene). The SRY gene, which is normally found on the Y chromosome, is misplaced in this disorder, almost always onto an X chromosome. A fetus with an X chromosome that carries the SRY gene will develop as a male despite not having a Y chromosome.

Males with 47,XYY syndrome have one X chromosome and two Y chromosomes in each cell, for a total of 47 chromosomes. It is unclear why an extra copy of the Y chromosome is associated with tall stature, learning problems, and other features in some boys and men.

Some males with 47,XYY syndrome have an extra Y chromosome in only some of their cells. This phenomenon is called 46,XY/47,XYY mosaicism.

48,XXYY syndrome is caused by the presence of an extra X chromosome and an extra Y chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone (a hormone that directs male sexual development) in adolescent and adult males. Extra copies of genes from the pseudoautosomal region of the extra X and Y chromosome contribute to the signs and symptoms of 48,XXYY syndrome; however, the specific genes have not been identified.

Y chromosome infertility is usually caused by deletions of genetic material in regions of the Y chromosome called azoospermia factor (AZF) A, B, or C. Genes in these regions are believed to provide instructions for making proteins involved in sperm cell development, although the specific functions of these proteins are unknown.

Deletions in the AZF regions may affect several genes. The missing genetic material likely prevents production of a number of proteins needed for normal sperm cell development, resulting in an inability to father children.

Chromosomal conditions involving the sex chromosomes often affect sex determination (whether a person has the sexual characteristics of a male or a female), sexual development, and the ability to have children (fertility). The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in these chromosomes.

Rarely, males may have more than one extra copy of the Y chromosome in every cell (polysomy Y). For example, the presence of two extra Y chromosomes is written as 48,XYYY. The extra genetic material in these cases can lead to skeletal abnormalities, decreased IQ, and delayed development, but the features of these conditions are variable.

Geneticists use diagrams called ideograms as a standard representation for chromosomes. Ideograms show a chromosome's relative size and its banding pattern. A banding pattern is the characteristic pattern of dark and light bands that appears when a chromosome is stained with a chemical solution and then viewed under a microscope. These bands are used to describe the location of genes on each chromosome.

You may find the following resources about the Y chromosome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

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Y chromosome - Genetics Home Reference

Proband – Wikipedia, the free encyclopedia

Proband, proposito (male proband), or proposita (female proband)[1] is a term used most often in medical genetics and other medical fields to denote a particular subject (person or animal) being studied or reported on.[2] On pedigrees, the proband is noted with a square (male) or circle (female) shaded accordingly. It is important to denote the proband, so that the relationship to other individuals can be seen and patterns established.

In most cases, the proband is the first affected family member who seeks medical attention for a genetic disorder.[2] Among the ancestors of the proband, there may be other subjects with the manifest disease, but the proband typically refers to the member seeking medical attention or being studied, even if affected ancestors are known. Often affected ancestors are unknown due to the lack of information regarding those individuals or about the disease at the time they lived. Other ancestors might be undiagnosed due to the incomplete penetrance or variable expressivity.

The diagnosis of a proband raises the index of suspicion for the proband's relatives and some of them may be diagnosed with the same disease. Conventionally, when drawing a pedigree chart, instead of the first diagnosed person, the proband may be chosen from among the affected ancestors (parents, grandparents) from the first generation where the disease is found.

The term proband is also used in genealogy, where it denotes the root node of an ahnentafel, also referred to as the progenitor.

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Proband - Wikipedia, the free encyclopedia

Workable male sterility systems for hybrid rice: Genetics …

Abstract

The exploitation of male sterility systems has enabled the commercialization of heterosis in rice, with greatly increased yield and total production of this major staple food crop. Hybrid rice, which was adopted in the 1970s, now covers nearly 13.6 million hectares each year in China alone. Various types of cytoplasmic male sterility (CMS) and environment-conditioned genic male sterility (EGMS) systems have been applied in hybrid rice production. In this paper, recent advances in genetics, biochemistry, and molecular biology are reviewed with an emphasis on major male sterility systems in rice: five CMS systems, i.e., BT-, HL-, WA-, LD- and CW- CMS, and two EGMS systems, i.e., photoperiod- and temperature-sensitive genic male sterility (P/TGMS). The interaction of chimeric mitochondrial genes with nuclear genes causes CMS, which may be restored by restorer of fertility (Rf) genes. The PGMS, on the other hand, is conditioned by a non-coding RNA gene. A survey of the various CMS and EGMS lines used in hybrid rice production over the past three decades shows that the two-line system utilizing EGMS lines is playing a steadily larger role and TGMS lines predominate the current two-line system for hybrid rice production. The findings and experience gained during development and application of, and research on male sterility in rice not only advanced our understanding but also shed light on applications to other crops.

Male reproductive development in plants involves several major developmental stages in series and along several cell lineage pathways, which include specification of stamen primordia, production of sporogenous cells, development of tapetum and microspore mother cells (MMCs), meiosis, formation of free haploid microspores, degeneration of tapetum and release of mature pollen grains (Goldberg et al. [1993]). Arrest of any of these steps can result in male sterility (MS), the failure to produce or release functional pollen grains. The phenotypic manifestations of MS may range from the complete absence of male organs, abnormal sporogenous tissues, to the inability of anther to dehisce or of pollen to germinate on compatible stigma (Chase et al. [2010]).

Evolutionarily, MS has been a subtle means by which plants prevent self-pollination and increase genetic diversity (Hanson [1991]). Over the past century, MS has facilitated the use of heterosis (or hybrid vigor) in crop production. Utilization of heterosis, the superior performance that the first generation (F1) hybrid demonstrates over its two parental lines, depends on the cost-effective production of hybrid seeds. Rice is a staple food crop for more than half of the worlds population; the use of heterosis in rice is second only to that in corn, among crop plants, and has played a significant role in further increasing rice yield after the first Green Revolution (Li et al. [2007]).

The success of hybrid rice has greatly promoted the search for and study of MS in rice. Several articles have recently reviewed the key genes and networks that determine male reproductive development, including the differentiation of sporophytic cells (Xing et al. [2011]; Feng et al. [2013]), specification of tapetum and microsporocyte cells (Zhang and Yang [2014]), and biosynthesis and regulation of sporopollenin and pollen exine development (Ariizumi and Toriyama [2011]; Liu and Fan [2013]). Mutations in such genes often result in MS in different forms, e.g. knockout mutation of CAP1, which encodes L-arabinokinase, resulted in collapsed abnormal pollens (Ueda et al. [2013]), and microsporeless anthers resulted from null mutations of MSCA1 in corn (Chaubal et al. [2003]) and MIL1 in rice (Hong et al. [2012]). As reviewed recently by Guo and Liu ([2012]) and Wang et al. ([2013b]), more than 40 MS genes have been cloned in rice. Shortly after the publication of these two reviews, several more rice fertility/sterility-related genes were reported, including genes underpinning tapetum function and hence pollen development (Liu and Fan [2013]; Ji et al. [2013]), genes required for the development of the anther and pollen (Moon et al. [2013]; Niu et al. [2013a], [b]), and genes for pollen germination and pollen tube growth (Huang et al. [2013b]). Clearly, the list is expected to grow in the near future. Although identifying genes and pathways is necessary in order to understand the underlying mechanisms in the development of the male reproductive system, not all MS mutations have practical use in hybrid crop production. This paper aims to analyze different MS systems that have been explored in hybrid rice production and summarize the latest understanding of their genetics, biochemistry, and biology. We also describe the dynamics of different MS systems in hybrid rice production in China over the past 30years.

Commercialization of any hybrid crop can only be achieved if reasonably priced technical solutions to hybrid seed production are available. In rice, hybrid seed production was first attempted using chemical hybridizing agent in the 1970s, but this approach was no longer used after MS systems became available. In order for an MS system to be workable for hybrid seed production, it must meet the following prerequisites: (1) complete and stable MS during hybrid seed production; (2) no substantial negative effect on MS and hybrid plants; (3) ability to multiply MS seeds through an intermediate genetic line (maintainer) or under particular environmental conditions; (4) ability to fully achieve fertility in hybrids. Therefore, although a number of MS systems have been generated during the past 40years, only those that met these requirements were adopted in hybrid production. So far, two distinct systems have been utilized in hybrid rice production: cytoplasmic male sterility (CMS) and environment-conditioned genic male sterility (EGMS).

Numerous CMS systems with different cytoplasm/nucleus combinations have been generated through backcross breeding. The cytoplasm and nucleus of CMS lines may originate from two different species, two different subspecies (indicajaponica), or two cultivars (indicaindica) (Virmani [1994]; Cheng et al. [2007]; Fujii et al. [2010]; Huang et al. [2013a],[b]). According to the China Rice Data Center (http://www.ricedata.cn/variety/ webcite), a total of 13 types of CMS lines have been used in developing hybrid cultivars, constituting an annual growing area of more than ~6800ha in at least 1year from 1983 to 2012 (data before 1983 are unavailable). The cytoplasm and nucleus sources of these 13 different CMS types are summarized in Table1, with BT-CMS and Dian1-CMS used in japonica and other systems used in indica hybrid rice production.

Table 1. Major male sterility systems utilized in hybrid rice production in China1

Both BT-CMS and Dian1-CMS contain indica cytoplasm and a japonica nucleus, whereas indica hybrid rice cultivars contain cytoplasm of diverse origins, including O. rufipogon (e.g., WA-CMS), various indica cultivars (e.g., GA-CMS, ID-CMS), and one japonica genotype (i.e., K-CMS) (Table1). It is not difficult to develop japonica CMS lines using cytoplasm from O. rufipogon or other indica lines, but such CMS has no practical use because no restorer lines have been identified in japonica rice.

WA-CMS lines are the most widely deployed lines in hybrid rice production (see below). Pollen abortion in WA-CMS occurs relatively early during microspore development, mainly at the uninucleate stage (Luo et al. [2013]), resulting in amorphous aborted pollen grains (Figure1). The pollen abortion is determined by the genotype of sporophytic tissues, not by the genotype of the pollen itself. That is, aborted pollens are only produced in plants with homozygous rf (restorer of fertility) gene (s) and CMS factor (s), but not in plants that are heterozygous at the Rf locus (Figure1, pollen fertility of F1 plants). All other CMS types of indica rice, except for HL-CMS, are similar to WA-CMS and are classified as WA-CMS-like types (Table1).

Figure 1. A schematic presentation of the five well-studied rice CMS types. Abbreviations for cytoplasm sources are RWA for wild-abortive Oryza rufipogon, RRA for red-awned O. rufipogon, and RW1 for Chinese wild rice (O. rufipogon) accession W1; IBT and ILD for indica Boro-II type and Lead rice, respectively. Nucleus sources are either indica (I) or japonica (J).

Pollen development in HL-CMS lines is arrested at the binucleate stage while that of BT-CMS arrested at the trinucleate stage. In contrast to the irregular morphology in WA-CMS, the pollen grains in both HL- and BT-CMS are spherical, and are unstainable or stainable, respectively, in I2-KI solution (Li et al. [2007]). Due to their deficiency in starch accumulation, pollen grains of BT-CMS is stained lighter than normal pollen grains (Figure1; Wang et al. [2006]); the intensity of staining, however, can be rather dark in some BT-CMS lines, almost indiscriminate from that of fertile pollen grains (Li et al. [2007]). Furthermore, unlike in WA-CMS, the MS of the BT- and HL-CMS lines is genetically controlled by gametophytic tissue (i.e., the haploid microspores; hence, only half of the pollen grains in F1 plants are viable) (Figure1). Dian1-CMS lines are very similar to BT-CMS in terms of pollen abortion and fertility restoration; they are classified as BT-like CMS (Table1).

The other MS system that is widely used in hybrid rice breeding is the EGMS system, which includes the photoperiod-sensitive genic male sterility (PGMS) and temperature-sensitive genic male sterility (TGMS) lines. PGMS lines are male-sterile under natural long day conditions and male fertile under natural short day conditions (Ding et al. [2012a]), whereas TGMS lines are sterile at high temperatures and fertile at lower temperatures (Xu et al. [2011]). Some lines, such as Peiai 64S, are male sterile under both long day and high temperature conditions and are referred to as P/TGMS lines (Zhou et al. [2012]).

The majority (>95%) of the EGMS lines utilized in hybrid rice production in China were derived from three independent progenitor lines, i.e., PGMS line Nongken 58S (NK58S) and TGMS lines Annong S-1 and Zhu 1S (Si et al. [2012]; Table1). Many lines derived from NK58S were P/TGMS or even TGMS (e.g., Guangzhan 63S), but the underlying mechanism leading to such dramatic changes has yet to be revealed (Lu [2003]).

Two other CMS types have the potential to be utilized in hybrid rice production. LD-CMS was obtained by Watanabe et al. ([1968]) by performing a backcross of the japonica variety Fujisaka 5 to the Burmese rice cultivar Lead Rice, giving it indica cytoplasm and a japonica nucleus (Figure1). The pollen grains of LD-CMS can be slightly stained with I2-KI, but they cannot germinate on stigmas (Figure1). The other CMS type is CW-CMS, which has the cytoplasm of O. rufipogon and a japonica nucleus. It produces morphologically normal pollen grains that can be stained darkly with I2-KI but lacks the ability to germinate (Figure1; Fujii and Toriyama [2005]). Both LD-CMS and CW-CMS are gametophytically controlled and hence half of the pollen grains of F1 plants are viable (Figure1).

A novel type of EGMS rice, known as rPGMS (reverse PGMS), may also be useful in hybrid rice system. This rice shows normal male fertility under long day conditions (>13.5h) but is male sterile under short day conditions (

The CMS is controlled by the interaction of cytoplasmic factors (now widely identified as mitochondrial genetic factors) and nuclear genes (Chen and Liu [2014]). As shown in Figure1, most CMS genes and their corresponding Rf genes have already been identified.

The genetic factors conditioning BT-, HL-, and WA-CMS are all chimeric genes, probably as a result of the rearrangement of the mitochondrial genome (Figure1). The BT-CMS gene, a mitochondrial open reading frame, orf79, was the first CMS gene identified (Akagi et al. [1994]) and subsequently cloned (Wang et al. [2006]) in rice. It is co-transcribed with a duplicated atp6 and hence is also known as B-atp6-orf79 (Figure1). Mitochondrial DNA analysis suggested that orf79 may also be responsible for Dian1-CMS (Luan et al. [2013]).

In HL-CMS lines, a chimeric ORF defined as atp6-orfH79 is the gene conditioning MS (Figure1). Although nucleotide sequences of orfH79 and orf79 share 98% identity, the intergenic regions between atp6-orfH79 and B-atp6-orf79 are significantly different, suggesting that atp6-orfH79 and B-atp6-orf79 diverged from a common ancestor (Yi et al. [2002]; Peng et al. [2010]; Hu et al. [2012]).

Two differentially expressed transcripts, one of them containing the ribosomal protein gene rpl5, were identified by examining the transcripts of the whole mitochondrial genomes of a WA-CMS line, Zhenshan 97A and of its maintainer, Zhenshan 97B (Liu et al. [2007]). The same group recently used rpl5 to probe the rearranged region in the mitochondrial genome and identified the WA-CMS gene, named WA352 (Wild Abortive 352), which is comprised of three rice mitochondrial genomic segments (orf284, orf224, and orf288) and one segment of unknown origin (Figure1), and encodes a 352-residue putative protein with three transmembrane segments (Luo et al. [2013]).

Previous work by Bentolila and Stefanov ([2012]), constituting the complete sequencing of male-fertile and male-sterile mitochondrial genomes, identified a WA-CMS-specific ORF, orf126, as a plausible candidate for the WA-CMS causative gene. This result is consistent with that of Luo et al. ([2013]) because orf126 is indeed part of WA352. Independently, Das et al. ([2010]) also identified rearrangements around the regions of atp6 and orfB. According to Luo et al. ([2013]), the atp6 locus is rearranged and directly linked to WA352, which is less than 20kb away from orfB in WA-CMS. Therefore, the results of these studies all corroborate one another.

The CMS gene that conditions LD-CMS has yet to be determined, but a B-atp6-orf79-like structure (L-atp6-orf79) was identified as the candidate (Figure1). In the mitochondrion of LD-CMS, there is only one copy of atp6 linked with orf79, which is different from BT-CMS and HL-CMS, the mitochondria of which retain a normal atp6 (N-atp6) in its origin position (Itabashi et al. [2009]).

No B-atp6-orf79-like structure was identified in the mitochondrion of CW-CMS, and the cytoplasmic factor (s) conditioning pollen sterility has yet to be determined (Fujii et al. [2010]).

It has been well documented that CMS can be restored by one or two Rf genes. A total of six Rf genes (Rf1a, Rf1b, Rf2, Rf4, Rf5 and Rf17) have been cloned (Figure1), and all except Rf17 are dominant.

Two fertility restoration genes, Rf1a and Rf1b, both encoding proteins containing pentatricopeptide repeat (PPR) motifs, were identified as being able to restore the fertility of BT-CMS (Kazama and Toriyama [2003]; Akagi et al. [2004]; Komori et al. [2004]; Wang et al. [2006]). Both Rf1a and Rf1b are located in the classical Rf1 locus. The rf1a allele differs from Rf1a due to a frameshift mutation that results in a truncated putative protein of 266 amino acids (Komori et al. [2004]; Wang et al. [2006]). A single-nucleotide polymorphism (SNP) of A1235-to-G causes the missense mutation of Rf1b to rf1b by substituting Asn412 for Ser (Wang et al. [2006]).

MS of HL-CMS can be restored by either Rf5 or Rf6, producing 50% normal pollen grains in F1 plants (Figure1). When both Rf5 and Rf6 are present, F1 plants may have 75% normal pollen grains (Huang et al. [2012]). Recently, the Rf5 gene was cloned and was identified to be the same gene as Rf1a or Rf1, which encodes the PPR protein PPR791 (Hu et al. [2012]). Sequencing of Rf5 and rf5 identified a single nucleotide T791-to-A alteration at the fourth PPR motif, which results in a nonsense mutation (TAT to TAA) in the HL-CMS line (Hu et al. [2012]).

WA-CMS can be restored by either Rf3 or Rf4, located on chromosome 1 and 10, respectively (Figure1). Numerous attempts have been made to delimit and ultimately clone the two genes without much success (Ahmadikhah and Karlov [2006]; Ngangkham et al. [2010]; Suresh et al. [2012]). The breakthrough was not made until very recently by Tang et al. ([2014]), who finally cloned the Rf4 gene, which also encodes a PPR protein.

Pollen fertility of LD-CMS can be restored by either Rf1 or Rf2; the latter has already been cloned (Figure1; Itabashi et al. [2009], [2011]). The Rf2 gene encodes a mitochondrial glycine-rich protein; replacement of isoleucine by threonine at amino acid 78 of the RF2 protein causes functional loss of the rf2 allele (Itabashi et al. [2011]). The CW-CMS is restored by a single nuclear gene, Rf17, which is a retrograde-regulated male sterility (rms) gene (Figure1; Fujii and Toriyama [2009]). Contrary to this finding, the same group suggested in earlier reports that two other genes, DCW11 and OsNek3, were related to pollen sterility in CW-CMS rice (Fujii and Toriyama [2008]; Fujii et al. [2009]). It is now evident that diversified mechanisms have been evolved for restoring fertility in CMS with multilayer interactions between the mitochondrial and nucleus genes (Chen and Liu [2014]).

In addition to the three major CMS types (i.e., WA-, BT-, and HL-CMS), several other CMS types were bred independently and have different cytoplasm and nucleus sources (Table1). Further studies revealed that both cytoplasm and nuclear genetic determinants are almost identical among some of them; hence, they may be classified into a common group.

First, the fertility restoration of Dian1-CMS is identical to that of BT-CMS, i.e., restorer lines of the latter are equally effective for the former, although Rf-D1 (t) was assigned for Dian1-CMS (Tan et al. [2004]). Subsequent cloning and characterization suggested that Rf-D1 is highly similar to Rf1a and has only one nucleotide difference (Zhu et al. [2009]).

Second, nine CMS types are classified as WA-like CMS (Table1) on the basis of the following observations: (1) WA352 is also identified in the GA-, D-, DA-, ID-, K-, and Y-CMS lines (Luo et al. [2013]); (2) Rf3 and Rf4 are effective for restoring the fertility of D-, DA-, ID-, GA-, Y-, and WA-CMS (Sattari et al. [2008]; Cai et al. [2014]); (3) these nine CMS types possess common mitotype-specific sequences that differ from fertile genotypes and from other CMS systems (e.g., BT-CMS, HL-CMS) (Xie et al. [2014]); and (4) they have identical or highly similar mitochondrial DNA (Luan et al. [2013]). However, we should not exclude the possibility that differences exist in their mitochondrial genomes. For example, Xu et al. ([2013]) recently indicated that male sterile cytoplasm has a marked effect on DNA methylation, which is enhanced to a much greater extent in WA- and ID-CMS than in G- and D-CMS.

Third, restorer lines containing Rf4 can often restore the fertility of BT-CMS and HL-CMS (but the opposite is not true). This effect might be explained by the following considerations: (1) Plants with Rf4 may also possess Rf1a and Rf1b. (2) The Rf4 allele has more functions than Rf1, and Rf4 itself has the ability to restore the fertility of both WA-CMS and BT-CMS. Notably, the recent cloning of Rf4 reveals that it also encodes a PPR protein, with high amino acid sequence identity with Rf1a of BT-CMS (Tang et al. [2014]).

Rice is a short-day plant; short day length accelerates panicle initiation and promotes flowering, but long day length delays or inhibits development. Likewise, relatively high temperatures promote rice growth and development. This reaction of plants to photoperiod and temperature is described as the first photoperiod/temperature reaction (FPTR, Yuan et al. [1993]). The P/TGMS lines described in this paper are those in which the male reproductive system responds to both day length and temperature, in the so-called second photoperiod/temperature reaction (SPTR).

Different EGMS lines may have very different fertility responses to photoperiod and temperature. Cheng et al. ([1996]) classified EGMS lines into three types: PGMS lines respond to either photoperiod or photoperiod-and-temperature, but not to temperature alone; TGMS lines respond to temperature, but not to photoperiod; P/TGMS lines are characterized by responding to photoperiod-and-temperature for their fertility transition.

During the past 20years, a number of EGMS lines have been identified that show genic MS under different conditions: long day (PGMS) or short day (reverse PGMS, rPGMS), high temperature (TGMS) or low temperature (rTGMS), and either long day or high temperature. In all these cases, the pollen fertility of EGMS systems is sporophytically controlled by nuclear gene (s), and the loci that control PGMS or TGMS, including rPGMS or rTGMS, have been mapped to different chromosomes (Si et al. [2012]; Sheng et al. [2013]; Zhang et al. [2013]). These mappings include PGMS genes: pms1, pms2, pms3; rPGMS genes: rpms1, rpms2, csa; TGMS genes: tms1, tms2, tms3, tms4, tms5, tms6, tms6(t), tms9; and P/TGMS genes: p/tms12-1, pms1(t). Some of these genes may be allelic and two of them, pms3 (p/tms12-1) (Ding et al. [2012a]; Zhou et al. [2012]) and csa (Zhang et al. [2013]), have been cloned.

NK58S, the first PGMS, was identified in 1973 from a Nongken58 population. It exhibits complete MS when growing under long days (day length more than 13h), but complete or partial fertility under short days (day length less than 13h) (Zhang and Yuan [1989]). However, Peiai 64S, developed from a cross between NK58S and Peiai 64 followed by backcrossing with Peiai 64, showed MS under both long day and high temperature conditions (Luo et al. [1992]). W6154S, also derived from NK58S, is a TGMS line. Zhang et al. ([1994]) identified two genes underlying the PGMS of NK58S. A study on the allelism of gene (s) for P/TGMS lines further showed that there were allelic male sterile genes between NK58S and its derivatives W6154S and Peiai 64S, but male sterile genes from the latter two are nonallelic, suggesting that NK58S has at least two genes underpinning its PGMS (Li et al. [2003]). Two recent independent studies identified the identical causative SNP for both the PGMS of NK58S (pms3, Ding et al. [2012a]) and the TGMS of Peiai 64S (p/tms12-1, Zhou et al. [2012]), although the identity of the locus containing the SNP was different (see below).

An rPGMS gene, carbon starved anther (csa), was recently cloned and may be potentially useful for diversification of the two-line hybrid rice system (Zhang et al. [2013]).

Several spontaneous TGMS mutants have been independently identified in breeding programs; more TGMS lines were selected in the progenies derived from NK58S (Si et al. [2012]). Genetic analyses indicated that the TGMS trait is under the control of single recessive genes. Among the fine-mapped TGMS genes, those of Annong S-1 (tms5), Guangzhan 63S (ptgms2-1), and Zhu 1S (tms9) are all located on chromosome 2. Whereas tms5 and ptgms2-1 were delimited to a partially overlapped region, tms9 was fine-mapped to a different segment near that of ptgms2-1/tms5 (Sheng et al. [2013]). Candidate genes were proposed for tms5 (OsNAC6; Yang et al. [2007]) and ptgms2-1 (a ribonuclease Z homolog, RNZ; Xu et al. [2011]), but none were suggested for tms9 (Sheng et al. [2013]). Our recent study, however, demonstrated that Annong S-1, Guangzhan 63S and Zhu 1S carry allelic TGMS genes (i.e. tms5, ptgms2-1, and tms9 are allelic), and further characterization of more than 300 non-EGMS and EGMS lines suggested that an identical nonsense mutation of the RNZ gene, i.e. RNZm.conditions the TGMS of Guangzhan 63S, Zhu 1S, Annong S-1, and a number of other TGMS lines (Zhang et al. [2014]).

Anther development in rice occurs over 14 stages (Zhang and Wilson [2009]), and the specification, development, and degradation of the anther are tightly regulated by various genes and pathways. Dysfunction of any gene may result in MS (Suzuki [2009]; Wilson and Zhang [2009]; Ariizumi and Toriyama [2011]; Feng et al. [2013]).

The development of pollen and degradation of the endothecium, middle layer, and tapetal cells are illustrated in Figure2. The tapetum is the nursing tissue inside the anther and plays a crucial role in the formation and development of pollen grains (Suzuki [2009]; Ariizumi and Toriyama [2011]). In wild-type plants, tapetum undergoes cellular degeneration by programmed cell death (PCD) and completely disappears by the time the mature pollen grains form. PCD is often observed in anther tissues by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Slight differences have been reported regarding the commencement of tapetal PCD in rice: One group (Ji et al. [2013]; Luo et al. [2013]) detected PCD as early as stage 8a (the dyad stage), whereas others (Li et al. [2006]; Ding et al. [2012a]) observed the earliest PCD occurring at stage 8b (the tetrad stage) or noted that it peaked at stage 9 (young microspore stage). The correct timing of tapetal PCD is important, and premature or delayed PCD is often associated with MS. Unlike most other rice MS mutants, which have delayed tapetal PCD (Li et al. [2006]; Ji et al. [2013]), certain EGMS and WA-CMS rice have premature tapetal PCD (Ding et al. [2012a]; Luo et al. [2013]; Figure2).

Figure 2. A schematic presentation of anther and pollen development in wild type (WT) rice, wild-abortive CMS (WA-CMS) rice, temperature- and photoperiod -sensitive genic male sterile (TGMS and PGMS) rice. Stage demarcation and developmental features of WT rice are adopted from Zhang and Wilson ([2009]); those of WA-CMS, TGMS and PGMS are according to Luo et al. ([2013]), Ku et al. ([2003]), and Ding et al. ([2012a]), respectively. Dots represent the DNA fragmentations detected by TUNNEL assay in tapetal cells undergoing programmed cell death. AP, aborted pollen; BP, binucleate pollen; E, epidermis; En, endothecium; ML, middle layer; T, tapetum; MMC, microspore mother cell; MC, meiotic cell; DY, dyad; Td: tetrad; MP, mature pollen.

The TGMS lines of Annong S-1, Xian 1S, and Guangzhan 63S have empty anthers (Ku et al. [2003]; Peng et al. [2010]; Xu et al. [2011]). Premature tapetal PCD initiates as early as the microspore mother cell (MMC) stage (stage 6) and continues until the tapetal cells are completely degraded in Annong S-1 grown under high temperature conditions (Ku et al. [2003]). The premature tapetal PCD resulted in early degradation of the tapetum, causing a decline in the supply of nutrition and other components (e.g. sporopollenin) to microspores, which were ruptured around stage 9. Consequently, no pollen grains were seen in the pollen sac in TGMS lines (Figure2).

Analysis of the PGMS line NK58S grown under long-day conditions demonstrated that tapetal PCD was already apparent at stage 7 and became intense from stage 8a to stage 9, much earlier than in NK58 (Ding et al. [2012a]). The premature tapetal PCD in NK58S resulted not only in pollen abortion but also incomplete degradation of tapetal cells at later stages (Figure2).

The different timings of premature tapetal PCD in TGMS and PGMS lines entail distinct consequences on pollen development in these two types (i.e., no pollen is formed in the pollen sac in TGMS lines and pollen abortion occurs in PGMS lines) (Figure2). However, it remains unclear whether the premature tapetal PCD is induced under MS-inducing conditions, because neither the PGMS gene nor the TGMS gene is involved directly or indirectly in any known PCD pathway.

In WA-CMS line Zhenshan 97A, tapetal PCD was also observed as early as stage 7 (Figure2), although it was not detected until stage 8a in its maintainer line Zhenshan 97B (Luo et al. [2013]). Tapetal PCD in WA-CMS rice started at the same stage as in PGMS rice, however, TUNEL assay indicated that DNA fragmentation only persisted to stage 9 in tapetal cells. Degradation of tapetal cells started as early as stage 8b, at which stage cytological observation showed debris was leaking from tetrads or tapetal cells. Consequently, tapetal cells degraded earlier than in wild type rice, and abnormal development of microspores could already be seen at stage 9 (Luo et al. [2013]; Figure2). The molecular mechanism leading to premature tapetal PCD in WA-CMS rice is well explained (see below).

In the BT-CMS system, CMS is known to be caused by a cytotoxic peptide, ORF79, encoded by a mitochondrial dicistronic gene B-atp6-orf79. ORF79 is a transmembrane protein; it is toxic to Escherichia coli (Wang et al. [2006]) and is also toxic to plant regeneration when it targets the mitochondria (Kojima et al. [2010]). ORF79 is accumulated specifically in microspores, despite its constitutive expression (Wang et al. [2006]), which provides a tight correlation between its accumulation and the phenotype of gametophytic MS. The molecular mechanism that regulates the expression of ORF79 and the way in which it causes the arrest of microspore development at the trinucleate stage are unknown.

BT-CMS is restored by two related PPR motif genes, Rf1a and Rf1b, by blocking ORF79 production through distinct modes of mRNA silencing: endonucleolytic cleavage of the dicistronic B-atp6-orf79 mRNA by RF1A and degradation by RF1B. In the presence of these two restorers, the Rf1a gene has an epistatic effect over the Rf1b gene in mRNA processing (Wang et al. [2006]). Further studies suggested that the RF1 protein mediates cleavage of the dicistronic mRNA by binding to the intergenic region, and the processed orf79 transcripts are degraded and unable to associate with ribosome. As a result, the orf79 expression is drastically reduced due to the processing of atp6-orf79 transcripts (Kazama et al. [2008]).

The mitochondrial dicistronic gene atp6-orfH79 is responsible for HL-CMS (Peng et al. [2010]), as proposed by Wang et al. ([2002]). Transcripts of orf79 and orfH79 differ in only five nucleotides, each of which results in distinctly different codon (Peng et al. [2010]). Like orf79, orfH79 is constitutively expressed; however, accumulation of ORFH79 is not limited to microspores as it is for orf79 in BT-CMS. Rather, it is accumulated mainly in the mitochondria in both vegetative and reproductive tissues, preferentially in sporogenous cells and root tips (Peng et al. [2010]). ORFH79 impairs mitochondrial function through its interaction with P61, a subunit of electron transport chain (ETC) complex III in HL-CMS rice (Wang et al. [2013a]). The interaction of ORFH79 and P61 significantly reduces the activity of ETC III through an as-yet-unknown mechanism, impairs the electron transport efficiency, and down-regulates the production of ATP. Concomitantly, more reactive oxygen species (ROS) are produced accompanying increased electron leakage from the ETC (Wang et al. [2013a]). The observations of increased ROS and preferential accumulation of ORFH79 in sporogenous cells are in accordance with a study that detected PCD in microspores of the HL-CMS line Yuetai A (Li et al. [2004]).

Unlike the RF1A-binding to B-atp6-orfH79 transcript, RF5 (the same protein of RF1A) is unable to bind to atp6-orfH79 transcript directly, due to its divergent intergenic region. Instead, a RF5s partner protein, GRP162, can bind to the atp6-orfH79 through an RNA recognition motif. These two proteins interact physically with each other in the so-called restoration of fertility complex (RFC), which can cleave atp6-orfH79 at a site 1169 nucleotides away from the atp6 start codon (Hu et al. [2012]). Additional components are predicted to participate in the RFC, because neither RF5 nor GRP162 can cleave the mRNA; it remains to be determined which factor of the RFC possesses the capacity as an endoribonuclease to process atp6-orfH79.

Another gene, Rf6, can also restore the fertility of HL-CMS, but little is known regarding its identity or the mechanism leading to fertility restoration (Huang et al. [2012]).

MS in WA-CMS rice is caused by WA352, which interacts with a nuclear-encoded integral protein of the inner mitochondrial membrane, OsCOX11. COX11 proteins are essential for the assembly of cytochrome c oxidase; they display high levels of conservation among eukaryotes and play a role in hydrogen peroxide degradation (Banting and Glerum [2006]). A significantly increased amount of ROS was observed in the tapetum of WA-CMS line Zhenshan 97A, but not in its maintainer, at the MMC stage (Luo et al. [2013]). Hence, it is assumed that the elevation of ROS in WA-CMS line, as a result of the interaction of WA352 with OsCOX11, prevents the normal function of OsCOX11 in H2O2 degradation. The excessive amount of ROS could further affect the mitochondrial membrane permeability and promote Cyt c release into the cytosol, triggering PCD (Luo et al. [2013]).

Both OsCOX11 and WA352 are constitutively expressed; however, while OsCOX11 protein is accumulated in all tissues, WA352 protein was detected only in anthers, not in leaves. In the anthers, WA352 was observed mainly in tapetal cells at the MMC stage and diminished after the meiotic prophase I stage. The tissue specificity and accumulation duration of WA352 are in good accordance with the occurrence of tapetal PCD as detected by TUNEL assay, the earliest PCD being observed as early as stage 7 of anther development (Figure2; Luo et al. [2013]). However, it is not known why WA352 only accumulates in tapetal cells at the MMC stage. Further studies are needed to uncover the molecular mechanism and genetic factor (s) regulating time-specific protein accumulation.

WA-CMS can be restored by either Rf3 or Rf4 (Figure1). The amounts of WA352 transcripts in the Rf4-carrying lines with WA-CMS cytoplasm were decreased to ~2025% of those in the WA-CMS line without Rf4, but were not affected in the Rf3-carrying lines. WA352 was undetectable in either Rf3- or Rf4-carrying young anthers (Luo et al. [2013]). These observations suggest different mechanisms of male fertility restoration be deployed by the two Rf genes: RF4 may cleave the WA352 transcript and RF3 may suppress its translation. In this regard, RF4 may function like that of RF1B, which mediates the degradation of atp6-orf79 mRNA, whereas RF3s mode of action would be distinctly different from those of RF1A and RF1B (see above).

Fertility of the LD-CMS can be restored by either Rf1 or Rf2 (Figure2). Although LD-CMS rice also possesses a chimeric atp6-orf79 dicistronic gene, L-atp6-orf79 (Figure2), the CMS in LD-cytoplasm is not caused by the accumulation of ORF79. The induction and restoration of LD-CMS are different from those in BT-CMS (Itabashi et al. [2009]). The Rf2 gene has already been cloned and is known to encode a mitochondrial glycine-rich protein, but the mechanism of CMS restoration has yet to be determined (Itabashi et al. [2011]).

As in LD-CMS, the cytoplasmic genetic factor that causes MS in CW-CMS has not been identified. However, its restorer of fertility gene, Rf17, is known to encode a 178-aa mitochondrial protein of unknown function. Rf17 is considered to be an rms gene, because its expression is regulated by the cytoplasmic genotype. The low expression of RMS in a restorer line of CW-CMS, probably due to a SNP in its promoter region, is speculated to restore compatibility between the nucleus and mitochondria, leading to male fertility (Fujii and Toriyama [2009]).

As mentioned above, a noncoding RNA was recently identified to underpin the PGMS of NK58S (pms3) and TGMS of Peiai 64S (p/tms12-1), with a common CG SNP as the causative element of P/TGMS (Ding et al. [2012a]; Zhou et al. [2012]). However, the functional element of this locus and its role in P/TGMS development were elucidated quite differently by the two groups.

Ding et al. ([2012a]) showed that the locus encodes a long noncoding RNA (lncRNA) designated LDMAR (long day-specific male fertility associated RNA), and they argued that a sufficient amount of LDMAR is essential for male fertility under long day conditions. The low abundance of LDMAR transcripts, rather than the CG SNP, is responsible for the PGMS of NK58S, because overexpression of the LDMAR transcript of NK58S restored the fertility of NK58S under long day conditions. They indicated that the low expression of LDMAR in NK58S is due to increased methylation in the promoter region, compared with NK58 (Ding et al. [2012a]). In a later study, they identified in the promoter region of LDMAR a siRNA called Psi-LDMAR, which is more abundant in NK58S than its wild type line (Ding et al. [2012b]). They suggested that the enhanced methylation in the LDMAR promoter region induced by the greatly enriched PsiLDMAR repressed the expression of LDMAR. However, several puzzles remain: First, as the authors noted, Psi-LDMAR is produced mainly in leaves, but regulation of fertility should reside in panicles (Ding et al. [2012b]); Second, the role of the CG SNP in increasing methylation of the promoter directly, or indirectly through the generation of Psi-LDMAR, was not addressed.

After identifying the lncRNA locus, Zhou et al. ([2012]) further narrowed down its functional form to a small, 21-nt RNA, designated as osa-smR5864w and osa-smR5864m for the wild-type and mutant allele, respectively. The small RNA may be a product of a 136-nt intermediate precursor. They speculated that osa-smR5864w may be the functional form and regulate male development under sterility-inducing conditions by cross-talking between the genetic networks and environmental conditions. However, no gene known to be involved in anther and pollen development has been shown to be the target of osa-smR5864w.

In addition to offering different explanations for the functional identity of the lncRNA locus, Ding et al. ([2012a]) and Zhou et al. ([2012]) made the following different observations: (1) LDMAR is expressed in all tissues and is relatively higher in panicles, whereas osa-smR5864w is mainly expressed in panicles; (2) Expression of LDMAR in NK58 is significantly higher under long days than under short days, and is significantly higher in NK58 than in NK58S under any day length, while expression of osa-smR5864w is almost independent of growing conditions. Consequently, Ding et al. ([2012a]) argued that occurrence of PGMS under long day resulted from lower expression of LDMAR rather than from the CG SNP; Zhou et al. ([2012]) inferred that it was the function rather than the amount of osa-smR5864w that determined PGMS in NK58S and TGMS in Peiai 64S.

Further studies will verify which hypothesis is correct, but the authors of this review are inclined to agree with Zhou et al. ([2012]) for the following reasons. (1) The functional importance of the CG SNP is explained in osa-smR5864w and osa-smR5864m, but it is very speculative in LDMAR. (2) The spatial expression of osa-smR5864w is more relevant to its function than is the spatial expression of LDMAR. (3) The possibility that LDMAR is a precursor of small RNA was not excluded. Indeed, Ding et al. ([2012a]) predicted and verified by RT-PCR that three small RNAs could be processed from a stem-loop structure involving 145 bases of LDMAR, and the smRNA-1 with the CG SNP is exactly the same as osa-smR5864.

The RNase Z enzyme is a highly conserved single-chain endoribonuclease that is expressed in all living cells. There are two classes of RNase Z proteins, long RNase ZL and short RNase ZS (Vogel et al. [2005]). RNase Z catalyzes the hydrolysis of a phosphodiester bond, producing 3-hydroxy and 5-phospho termini as it participates in tRNA maturation by cleaving off a 3 trailer sequence (Mayer et al. [2000]). The first RNase Z gene was cloned from Arabidopsis (Schiffer et al. [2002]); studies of homologous genes in various species have revealed that RNase Z could cleave a broader spectrum of substrates, including coding and noncoding RNAs (Xie et al. [2013]).

In plants, RNase Z is described using a prefix for the species, followed by TRZ (e.g., AthTRZ and OsaTRZ are the RNase Z genes in Arabidopsis and rice, respectively) (Fan et al. [2011]). The rice genome has three RNase Z genes: OsaTRZ1 (LOC_Os02g12290) and OsaTRZ2 (LOC_Os09g30466) encoding RNase ZS, and OsaTRZ3 (LOC_Os01g13150) encoding RNase ZL (Fan et al. [2011]). OsaTRZ2 contributes to chloroplast biogenenesis and homozygous OsaTRZ2 mutants are albino with deficient chlorophyll content due to the arrest of chloroplast development at an early stage (Long et al. [2013]). As indicated above, a nonsense mutation of OsaTRZ1 (RNZm) could be responsible for the TGMS traits in rice (Zhang et al. [2014]). Although it is unclear how this mutation leads to TGMS, the following observations in other species suggest a logical pathway by which the RNZm mutation could result in TGMS. First, the Arabidopsis genome has four RNase Z genesAthTRZ1 and AthTRZ2 for RNase ZS, and AthTRZ3 and AthTRZ4 for RNase ZLbut only the chloroplast-localized AthTRZ2 is essential. Deletions of the other three are not lethal (Canino et al. [2009]), suggesting that the null mutation of OsaTRZ1 will also not be lethal for rice development, a phenomenon that fits RNZm mutants. Second, it has been proven that conditional knockout at gametogenesis of Drosophila RNZ leads to thinner testes and lack of post-meiotic germ cells (Xie et al. [2013]), a phenomenon similar to that observed in TGMS rice: premature degeneration of tapetal cells and lack of pollen in the pollen sac (Figure2).

Because the function of TRZ genes has been assigned recently, very limited references are available for a thorough judgment of the possible functions of OsaTRZ1 and its involvement in male gametophyte formation. Further studies are needed to unveil the molecular mechanism of TGMS and to elucidate the functions and working mechanisms of TRZ1 genes in plants in general and in rice in particular.

Epigenetic regulation has recently been identified to play an important role in gene expression. DNA methylation is known to play a role in fertility transformation of rice P/TGMS (Ding et al. [2012b]). In addition, Chen et al. ([2014]) further observed that the DNA methylation level of P/TGMS line Peiai 64S was lower under low temperatures and short-day conditions (associated with fertility) than under high temperatures and long-day conditions (associated with sterility), suggesting that DNA methylation may be involved in the sterilityfertility transition of Peiai 64S in two different environmental profiles. Similarly, Xu et al. ([2013]) detected DNA methylation sites that were specific to CMS lines or maintainer lines (B lines), implying a specific relationship between DNA methylation at these sites and male-sterile cytoplasm, as well as a relationship with MS. Furthermore, Xu et al. ([2013]) demonstrated that DNA methylation was markedly affected by male-sterile cytoplasms (i.e., WA- and ID-type cytoplasms affected methylation to a much greater degree than did G- and D-type cytoplasms, although there were few differences at the DNA level). Therefore, studies on epigenetic regulation may increase our understanding of the mechanisms regulating MS and restoration.

Since the first WA-CMS-based hybrid rice was commercialized in the 1970s in China, several hundred CMS and EGMS lines have been developed, and some of them are currently or were once used in rice production. Although it is known that WA-CMS is the most widely used CMS in China (Cheng et al. [2007]) and in India (Khera et al. [2012]), so far no report has documented the dynamic changes of different MS systems in rice production. The China Rice Data Center (http://www.ricedata.cn/ webcite) has kept records of the annual planting area of rice cultivars grown in areas of at least ~6800ha from 1983 to the present day. Therefore, we are able to analyze the growing areas under hybrid rice cultivation over the past 20years (19832012). The following is the information extracted from the original data.

Two-line system hybrid rice was not commercialized until 1993; however, it has since played a steadily larger role in hybrid rice production (Figure3a). In 2012, two-line system hybrid rice already covered a total growing area of ~3.3 million ha, about one-third of the total hybrid rice growing area (~10 million ha) (Figure3a) (Note: only the hybrids that had been grown in areas more than 50,000ha were included in Figure3).

Figure 3. Planting areas covered by different types of hybrid rice in China (19832012).a, Hybrids based on BT-, HL-, and WA-CMS lines as well as EGMS (environment-conditioned genic male sterility). b, Hybrids based on different CMS types with similar features to WA-CMS. For definition of different CMS types see Table1. Note the data were composed of hybrid rice cultivars that had grown in more than 50,000ha (1983 to 2012) in this figure, cultivars with less growing area were not included.

In order to avoid the genetic vulnerability such as the crop failure of hybrid corn based on T-CMS in the 1970s, Chinese rice breeders from the very beginning have been trying to develop new types of CMS lines and to diversify the cytoplasm sources of these lines. Hence, ~15 new CMS sources other than WA-CMS have been developed and deployed in hybrid rice production. These sources may be classified into three primary groups: BT- and BT-like CMS, HL-CMS, and WA- and WA-like CMS (Table1).

BT-CMS-based japonica hybrid rice was successfully developed in the 1970s, only a few years after WA-CMS-based indica hybrids. However, the planting area was very limited compared with the latter (Figure3a). Within the BT- and BT-like category, Dian1-CMS hybrids are steadily replacing BT-CMS hybrids; the former now comprise ~90% of cultivation (data not shown).

Within the WA-CMS and the WA-CMS-like categories, there are more than a dozen subtypes of CMS lines. Although WA-CMS still dominates among the subtypes, its absolute dominance has been diminishing since the mid-1990s, and now it represent less than 55% of the total CMS-based hybrid rice (Figure3b). Indeed, this category represents almost the same proportion of all CMS rice because BT- and HL-CMS have a very low percentage of the total CMS (Figure3a).

CMS was used initially in the development of hybrid rice in the so-called three-line hybrid system, but EGMS is becoming more popular in hybrid rice production since the two-line hybrid system, in which the EGMS lines are used, has advantages of a wider range of restoring lines, more freely combinations and simple breeding program. CMS is conditioned by chimeric recombinant mitochondrial genes; the fertility of CMS lines may be restored by Rf genes. EGMS is underpinned by genes for non-coding RNA, transcriptional factors and RNA-processing enzymes. Different MS systems for rice have undergone dynamic changes in practical application in China.

B line: Maintainer line

CMS: Cytoplasmic male sterility

csa: Carbon starved anther

EGMS: Environment-conditioned genic male sterility

ETC: Electron transport chain

F1: First generation

FPTR: First photoperiod/temperature reaction

LDMAR: Long day specific male fertility associated RNA

lncRNA: Long non-coding RNA

lncRm: lncR with C-to-G SNP that underpins the PGMS phenotype

MMCs: Microspore mother cells

MS: Male sterility

NK58: Nongken58

P/TGMS: Photoperiod-and temperature-sensitive genic male sterility

PCD: Programmed cell death

PGMS: Photoperiod-sensitive genic male sterility

PPR: Pentatricopeptide repeat

Rf: Restorer of fertility gene

RFC: Restoration of fertility complex

RMS: Retrograde-regulated male steriity

RNZ: Ribonuclease Z homolog

RNZm: OsaTRZ1 carrying a null mutation that underpins the TGMS phenotype

ROS: Reactive oxygen species

rPGMS: Reverse PGMS

rTGMS: Reverse TGMS

SNP: Single-nucleotide polymorphism

SPTR: Second photoperiod/temperature reaction

TGMS: Temperature-sensitive genic male sterility

TUNEL: Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

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Workable male sterility systems for hybrid rice: Genetics ...

Sensorineural deafness and male infertility – Genetics …

Reviewed April 2010

Sensorineural deafness and male infertility is a condition characterized by hearing loss and an inability to father children. Affected individuals have moderate to severe sensorineural hearing loss, which is caused by abnormalities in the inner ear. The hearing loss is typically diagnosed in early childhood and does not worsen over time. Males with this condition produce sperm that have decreased movement (motility), causing affected males to be infertile.

The prevalence of sensorineural deafness and male infertility is unknown.

Sensorineural deafness and male infertility is caused by a deletion of genetic material on the long (q) arm of chromosome 15. The signs and symptoms of sensorineural deafness and male infertility are related to the loss of multiple genes in this region. The size of the deletion varies among affected individuals. Researchers have determined that the loss of a particular gene on chromosome 15, the STRC gene, is responsible for hearing loss in affected individuals. The loss of another gene, CATSPER2, in the same region of chromosome 15 is responsible for the sperm abnormalities and infertility in affected males. Researchers are working to determine how the loss of additional genes in the deleted region affects people with sensorineural deafness and male infertility.

Read more about the CATSPER2 and STRC genes and chromosome 15.

Sensorineural deafness and male infertility is inherited in an autosomal recessive pattern, which means both copies of chromosome 15 in each cell have a deletion. The parents of an individual with sensorineural deafness and male infertility each carry one copy of the chromosome 15 deletion, but they do not show symptoms of the condition.

Males with two chromosome 15 deletions in each cell have sensorineural deafness and infertility. Females with two chromosome 15 deletions in each cell have sensorineural deafness as their only symptom because the CATSPER2 gene deletions affect sperm function, and women do not produce sperm.

These resources address the diagnosis or management of sensorineural deafness and male infertility and may include treatment providers.

You might also find information on the diagnosis or management of sensorineural deafness and male infertility in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook. Read more about genetic testing, particularly the difference between clinical tests and research tests.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

You may find the following resources about sensorineural deafness and male infertility helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

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Sensorineural deafness and male infertility - Genetics ...

Cloning Myths – Learn Genetics

In What is cloning? we learned what it means to clone an individual organism. Given its high profile in the popular media, the topic of cloning brings up some common, and often confusing, misconceptions.

Let's say you wanted a clone to do your homework. After reviewing What is Cloning? and Click and Clone, you've figured out, generally, how to make a clone. Knowing what you know, do you think this approach would really help you finish your homework...this decade?

A common belief is that a clone, if created, would magically appear at the same age as the original. This simply isn't true. You remember that cloning is a way to create an embryo, not a full-grown individual. The embryo, once created, must develop exactly the same way as a regular embryo made by joining egg and sperm. Your clone would need a surrogate mother and ample time to grow and fully develop into an individual.

Your beloved cat Frankie has been a loyal companion for years. Recently, though, Frankie has been showing signs of old age, and you realize that your friend's days are numbered. You can't bear the thought of living without her, so you contact a biotechnology company that advertises pet cloning services. For a fee, this company will clone Frankie using DNA from a sample of her somatic cells. You're thrilled: you'll soon have a carbon copy of Frankiewe'll call her Frankie #2and you'll never have to live without your pal! Right?

Not exactly. Are you familiar with the phrase "nature versus nurture?" Basically, this means that while genes help determine traits, environmental influences have a considerable impact on shaping an individual's physical appearance and personality. For example, do you know any identical twins? They are genetically the same, but do they really look and act exactly alike?

So, even though Frankie #2 is genetically identical to the original Frankie, she will grow and develop in a completely different environment than the original Frankie, she will have a different mother, and she will be exposed to different experiences throughout her development and life. Therefore, there is only a slim chance that Frankie #2 will closely resemble the Frankie you know and love.

Another difference between a clone and the original is the mitochondria. Mitochondria are organelles that sit inside nearly every cell. Their job is to burn fuel (from the food we eat) to make energy. Mitochondria have their own chromosome, made of DNA and divided into genes, and they divide as our cells divide.

We get our mitochondria from our mothers. Egg cells are packed with mitochondria, which are copied and distributed to new cells as they form. When a clone is made using nuclear transfer, the egg cell that's used to receive the donor nucleus is already filled with mitochondria contributed by the egg donor. As the clone develops, its cells will be filled with these mitochondriaand their genesrather than the mitochondria from the DNA donor.

Nature vs. Nurture. Find out why twins become increasingly different as they age in Epigenetics.

Clones can be made in the lab through artificial embryo twinning or nuclear transfer. But these aren't the only ways to make a clone.

Clones are simply identical genetic copies. Many organisms reproduce through cloning as a matter of course, through a process called asexual reproduction. Bacteria, yeast, and single-celled protozoa multiply by making copies of their DNA and dividing in two. Redwood and aspen trees send up shoots from their roots, which grow into trees that are genetically identical to the parent.

In the animal world, the eggs of female aphids grow into identical genetic copies of their motherwithout being fertilized by a male. If a starfish is chopped in half, both pieces can regenerate, forming two complete, genetically identical individuals. Even mammals form natural clones: identical twins are a common example in many species.

Learn more about Sexual and Asexual Reproduction.

Humans have been cloning plants for at least a couple thousand years. Many of the fruits we eatincluding bananas, grapes, and applescome from artificially created clones. Unlike the complex process of cloning a mammal, cloning a plant can be as simple as cutting a branch from one tree and grafting it onto another.

Animal cloning also has a long history. Artificial embryo twinning, which involves dividing an early embryo to form separate, genetically identical organisms, was first done in a vertebrate over 100 years ago. And the first successful nuclear transfer was done in a frog in the 1970s.

Learn more about The History of Cloning.

While animal cloning still has a high failure rate, and some well-known clones (including Dolly the sheep) have had health problems, clones are not necessarily "damaged." Many live long, healthy lives. One racing mule clone was at one time ranked third in the world. And a barrel-racing horse clone was not only born healthy, but at two years old he was also collecting a stud fee of $4,000 for his owners.

One reason for cloning's high failure rate seems to be incomplete resetting of the somatic cell's DNA. During egg and sperm formation, DNA is "reset" to a baseline or embryonic state. As the embryo develops, cells begin to differentiate into muscle, nerve, liver, and other types. Part of the differentiation process involves adding and removing chemical tags on the DNA, which keeps genes turned "on" that are necessary for the function of that cell type and keeps others turned "off."

Learn more about this process in Epigenetics.

APA format: Genetic Science Learning Center (2014, June 22) Cloning Myths. Learn.Genetics. Retrieved September 25, 2015, from http://learn.genetics.utah.edu/content/cloning/cloningmyths/ MLA format: Genetic Science Learning Center. "Cloning Myths." Learn.Genetics 25 September 2015 Chicago format: Genetic Science Learning Center, "Cloning Myths," Learn.Genetics, 22 June 2014, (25 September 2015)

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Cloning Myths - Learn Genetics

Hormone and genetic study in male to female transsexual …

BACKGROUND:

Data of the literature demonstrated controversial results of a correlation between transsexualism and genetic mutations.

To evaluate the hormone and gene profile of male-female (M-F) transsexual.

Thirty M-F transsexuals aged 24-39. Seventeen had already undergone sex reassignment surgery, 13 were awaiting. All subjects had been undergoing estrogen and antiandrogen therapy. We studied hormones of the hypothalamus- pituitary-testicular axis, thyroid and adrenal profile, GH basal and after GHRH stimulation, IGF-I. The gene study analyzed SRY, AR, DAX1, SOX9, AZF region of the Y chromosome.

Pre-surgery subjects had elevated PRL, reduced testosterone and gonadotropins. Post-surgery subjects showed reduced androgens, a marked increase in LH and FSH and normal PRL. Cortisol and ACTH were similar to reference values in pre- and post-surgery patients. There was a marked increase in the baseline and post-stimulation GH values in 6 of the 13 pre-surgery patients, peaking at T15. IGF-I was similar to reference values in both groups except for one post-surgery patient, whose level was below the normal range. There were no polymorphisms in the amplified gene region for SOX9, and a single nucleotide synonimous polymorphism for DAX1. No statistically significant differences were seen in the mean of CAG repeats between controls and transsexual subjects. SRY gene was present in all subjects. Qualitative analysis of the AZFa, AZFb, and AZFc regions did not reveal any microdeletions in any subject.

This gender disorder does not seem to be associated with any molecular mutations of some of the main genes involved in sexual differentiation.

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Hormone and genetic study in male to female transsexual ...

Are People Born Gay? Genetics and Homosexuality

Introduction

There is a common belief among liberals that people are born either gay or straight. Conservatives tend to believe that sexual orientation is actually sexual preference, which is chosen by the individual. This page represents a review of the scientific literature on the basis for homosexual orientation.

Are people born gay or straight? Much of the current media sources assume the question is a solved scientific problem with all the evidence pointing toward a biological (probably genetic) basis for a homosexual orientation. Contrary to this perception, the question has been poorly studied (or studied poorly), although there is some evidence on both sides of question. In addition, many of the initial studies, which were highly touted by the media as "proof" for a biological basis for homosexuality, have been contradicted by later, more thorough studies. This evidence falls into four basic categories:

Until a few years ago, sexual orientation used to be called sexual preference. Obviously, the two terms denote significant differences in the the manner by which sexuality develops. A preference is something that is chosen, whereas orientation is merely something that defines us. The differences are potentially important regarding how the law applies to those who are gay. If homosexuality is not chosen, but actually is a biologically-determined characteristic over which we have no choice, then laws should not treat gays and straights differently, since homosexuality would be equivalent to one's race, over which we have no control.

Since sexual attraction begins in the brain, researchers first examined the question of sexual orientation by comparing the anatomy of brains from males and females. These studies showed that male and female brains showed sexual dimorphism in the pre-optic area of the hypothalamus, where males demonstrated a greater than two-fold difference in cell number and size compared to females.1 A second study found that two of four Interstitial Nuclei of the Anterior Hypothalamus (INAH) were at least twice as large in males as females.2 Since the INAH was involved in sexual dimorphism, it was hypothesized by Simon LeVay that there might be differences in this region in heterosexual vs. homosexual men. Postmortem examination of the brains of AIDS patients vs. control male subjects (presumed to be heterosexual) showed that the presumably heterosexual men exhibited INAH3 that were twice the size of both females and presumably homosexual men who had died of AIDS.3 The study has been criticized for its uncertainty of sexual orientation of the subjects, and potential complications caused by the AIDS virus (which does infect the human brain), and also by lowered testosterone levels found in AIDS patients. A popularized Newsweek cover story, "Is This Child Gay?"4 characterized LeVay as a "champion for the genetic side," even though the study involved no genetic data at all.

A subsequent study by Byne, et al. examined the question of INAH3 size on the basis of sex, sexual orientation, and HIV status.5 The study found large differences in INAH3 volume on the basis of sex (with the male INAH3 being larger than the female INAH3). However, the volume of IHAH3 was decreased in male heterosexual men who had contracted AIDS (0.108 mm3 compared with 0.123 mm3 in male controls). There was no statistically significant difference between IHAH3 sizes of male heterosexuals vs. male homosexuals who had contracted AIDS (0.108 mm3 and 0.096 mm3, respectively). The study also found that there were no differences in the number of neurons in the INAH3 based upon sexual orientation, although researchers found significant differences between males and females, as in other studies.5 It was obvious from this study that LeVay's study was fatally flawed due to the AIDS complication, and that there were no differences in the INAH3 based upon sexual orientation.

The role of the hypothalamus in sexual orientation was further studied by Swaab, et al. Other researchers had hypothesized that differentiation of the hypothalamus occurred before birth. However, Swaab's study showed that the sexually dimorphic nucleus (SDN) of more than 100 subjects decreased in volume and cell number in the females only 2-4 years postnatal. This finding complicated the findings of the brain studies, since not only chemical and hormonal factors, but also social factors, might have influenced this process.6

A study by Allen and Gorski examined the anterior commissure of the brain, finding that females and homosexual males exhibited a larger size than heterosexual males.7 However, later studies using larger sample sizes found no such differences.8

Complicating the issue of brain differences between homosexuals and heterosexuals is the problem that sexual experiences themselves can affect brain structure.9 So, the question will always be whether homosexual practice changes the brain or whether the brain results in homosexual practice.

Since sexual differentiation occurs within the womb, as a result of hormonal influences, it has been hypothesized that homosexuality may result from a differential hormone balance in the wombs of those who eventually exhibit a homosexual orientation. Since hormonal levels within the womb are not available, proxies for hormonal influences have been used to examine the question of how hormonal influences might impact sexual orientation. These proxies include differences in skeletal size and shape, including the ratio of the long bones of the arms and legs relative to arm span or stature and the hand bones of adults (the ratio of the length of the various phalanges).

Studies have shown that ratios of digit length are predictors of several hormones, including testosterone, luteinizing hormone and estrogen.10 In women, the index finger (2D, second digit) is almost the same length as the fourth digit (4D). However, in men, the index finger is usually shorter than the fourth. It has been shown that this greater 2D:4D ratio in females is established in two-year-olds. It has been hypothesized that the sex difference in the 2D:4D ratio reflects the prenatal influence of androgen on males. A study by Williams, et al. showed that the 2D:4D ratio of homosexual men was not significantly different from that of heterosexual men for either hand.11 However, homosexual women displayed significantly smaller 2D:4D ratios compared with heterosexual women (see figure to right). It has been hypothesized that women exposed to more androgens in the womb tend to express a homosexual orientation. However, since these hormone levels were never measured, one is left with the proxy of finger lengths as a substitute. Studies have found that the more older brothers a boy has, the more likely he is to develop a homosexual orientation.12 This study also found that homosexual men had a greater than expected proportion of brothers among their older siblings (229 brothers: 163 sisters) compared with the general population (106 males: 100 females). Males who had two or more older brothers were found to have lower 2D:4D ratios,11 suggesting that they had experienced increased androgens in the womb. Why increased androgens would predispose both males and females to be homosexual was not explained in the study.

Another study examined the length of long bones in the arms, legs and hands. Both homosexual males and heterosexual females had less long bone growth in the arms, legs and hands, than heterosexual males or homosexual females.13 Accordingly, the researchers hypothesized that male homosexuals had less androgen exposure during development than male heterosexuals, while female homosexuals had greater steroid exposure during development than their heterosexual counterparts. Of course, with regard to male homosexuality, this study directly contradicted the presumed results of the Williams study above, which "showed" that males with multiple older brothers (who tended to be homosexual) experienced increased androgen exposure.

A study of one homosexual vs. two heterosexual male triplets found that the homosexual triplets scored more on the female side of the Masculinity-Femininity scale of the Minnesota Multiphasic Personality Inventory,14 suggesting a possible hormonal influence (decreased androgens) involved in male homosexual orientation.

All of the studies reporting possible hormonal influence on homosexuality suffer from the lack of any real evidence that hormones actually play any role in sexual orientation. The fact that contradictory studies report increased11,15 vs. decreased13-14 androgens as a basis for homosexuality doesn't provoke confidence that the proxies are really true. Obviously, a study that documented real hormone levels, as opposed to proxies, would probably provide more definitive data.

Studies involving a rare hormonal imbalance, congenital adrenal hyperplasia (CAH), caused by defective 21-hydroxylase enzyme, suggest that hormonal abnormalities can influence sexual orientation. CAH results in increased production of male hormones during development. In males, increased androgens has little effect. However, female fetuses that develop in this environment develop ambiguous external genitalia, which complicates subsequent development. In utero treatment with dexamethasone reduces the androgen imbalance, resulting in an individual who is genetically and phenotypically female. However, dexamethasone treatment also results in reduced homosexual orientation among treated females,16 suggesting that some homosexuality may result from hormonal influences during development. Homosexual rights groups have suggested that dexamethasone treatment not be given, because it reduces homosexual orientation in females affected by CAH.

The observation that familial factors influence the prevalence of homosexuality led to a the initiation of number of twin studies, which are a proxy for the presence of possible genetic factors. Most of these early studies suffered from methodological flaws. Kallmann sampled subjects from correctional and psychiatric institutionsnot exactly representative "normal" populations.17 Bailey et al. published a number of studies in the early 1990's, examining familial factors involved in both male and female homosexuality. These studies suffered from the manner in which subjects were recruited, since the investigators advertised in openly gay publications, resulting in skewed populations.18 Later studies by the same group did not suffer from this selection bias, and found the heritability of homosexuality in Australia was up to 50 and 60% in females but only 30% in males.19

A study by Kendler et al. in 2000 examined 1,588 twins selected by a random survey of 50,000 households in the United States.20 The study found 3% of the population consisted of non-heterosexuals (homosexuals and bisexuals) and a genetic concordance rate of 32%, somewhat lower than than found in the Australian studies. The study lost statistical significance when twins were broken down into male and female pairs, because of the low rate (3%) of non-heterosexuals in the general U.S. population.

A Finnish twin study reported the "potential for homosexual response," not just overt homosexual behavior, as having a genetic component.21

On a twist on homosexual twin studies, an Australian research group examined the question of whether homophobia was the result of nature or nurture.22 Surprisingly, both familial/environmental and genetic factors seemed to play a role as to whether or not a person was homophobic. Even more surprising, a separate research group in the U.S. confirmed these results (also adding that attitudes towards abortion were also partly genetic).23 Now, even homophobes can claim that they were born that way!

Twin studies suffer from the problem of trying to distinguish between environmental and genetic factors, since twins tend to live within the same family unit. A study examining the effect of birth order on homosexual preference concluded, "The lack of relationship between the strength of the effect and degree of homosexual feelings in the men and women suggests the influence of birth order on homosexual feelings was not due to a biological, but a social process in the subjects studied."12 So, although the twin studies suggest a possible genetic component for homosexual orientation, the results are certainly not definitive.

An examination of family pedigrees revealed that gay men had more homosexual male relatives through maternal than through paternal lineages, suggesting a linkage to the X chromosome. Dean Hamer24 found such an association at region Xq28. If male sexual orientation was influenced by a gene on Xq28, then gay brothers should share more than 50% of their alleles at this region, whereas their heterosexual brothers should share less than 50% of their alleles. In the absence of such an association, then both types of brothers should display 50% allele sharing. An analysis of 40 pairs of gay brothers and found that they shared 82% of their alleles in the Xq28 region, which was much greater than the 50% allele sharing that would be expected by chance.25 However, a follow-up study by the same research group, using 32 pairs of gay brothers and found only 67% allele sharing, which was much closer to the 50% expected by chance.26 Attempts by Rice et al. to repeat the Hamer study resulted in only 46% allele sharing, insignificantly different from chance, contradicting the Hamer results.27 At the same time, an unpublished study by Alan Sanders (University of Chicago) corroborated the Rice results.28 Ultimately, no gene or gene product from the Xq28 region was ever identified that affected sexual orientation. When Jonathan Marks (an evolutionary biologist) asked Hamer what percentage of homosexuality he thought his results explained, his answer was that he thought it explained 5% of male homosexuality. Marks' response was, "There is no science other than behavioral genetics in which you can leave 97.5% of a phenomenon unexplained and get headlines."29

A study of 13,000 New Zealand adults (age 16+) examined sexual orientation as a function of childhood history.30 The study found a 3-fold higher prevalence of childhood abuse for those who subsequently engaged in same sex sexual activity. However, childhood abuse was not a major factor in homosexuality, since only 15% of homosexuals had experienced abuse as children (compared with 5% among heterosexuals).30 So, it would appear from this population that only a small percentage of homosexuality (~10%) might be explained by early childhood abusive experiences.

If homosexual orientation were completely genetic, one would expect that it would not change over the course of one's life. For females, sexual preference does seem to change over time. A 5-year study of lesbians found that over a quarter of these women relinquished their lesbian/bisexual identities during this period: half reclaimed heterosexual identities and half gave up all identity labels.31 In a survey of young minority women (16-23 years of age), half of the participants changed their sexual identities more than once during the two-year survey period.32 In another study of subjects who were recruited from organizations that serve lesbian/gay/bisexual youths (ages 14 to 21 years) in New York City, the percentage that changed from a lesbian/gay/bisexual orientation to a heterosexual orientation was 5% over the period of just 12 months (the length of the survey).33 Other studies have confirmed that sexual orientation is not fixed in all individuals, but can change over time, especially in women.34 A recent example of an orientation change occurred with The Advocate's "Person of the Year" for 2005. Kerry Pacer was the youngest gay advocate, chosen for her initiation of a "gay-straight alliance" at White County High School in Cleveland, Georgia. However, four years later, she is raising her one year old daughter, along with the baby's father.35 Another former lesbian, British comedienne Jackie Clune, spent 12 years in lesbian relationships before marrying a man and producing 4 children.36 Michael Glatze came out at age 20 and went on to be a leader in the homosexual rights movement. At age 30, he came out in the opposite direction, saying, "In my experience, "coming out" from under the influence of the homosexual mindset was the most liberating, beautiful and astonishing thing I've ever experienced in my entire life."37 A 2011 study of Christian gays who wanted to change their sexual orientation found that 23% of the subjects reported a successful "conversion" to heterosexual orientation and functioning, while an additional 30% reported stable behavioral chastity with substantive dis-identification with homosexual orientation.38 However, 20% of the subjects reported giving up on the process and fully embraced a gay identity, while another 27% fell in between the two extremes.38 Obviously, for at least some individuals, being gay or straight is something they can choose.

The question of nature vs. nurture can also be seen by examining children of homosexual vs. heterosexual parents. If homosexuality were purely biological, one would expect that parenting would not influence it. Paul Cameron published a study in 2006 that claimed that the children of homosexual parents expressed a homosexual orientation much more frequently than the general population.39 Although claims of bias were made against the study, another study by Walter Schuum in 2010 confirmed Cameron's results by statistically examining the results of 10 other studies that addressed the question.40 In total, 262 children raised by homosexual parents were included in the analysis. The results showed that 16-57% of such children adopted a homosexual lifestyle. The results were even more striking in daughters of lesbian mothers, 33% to 57% of whom became lesbians themselves. Since homosexuals makeup only ~5% of the population, it is clear that parenting does influence sexual orientation.

It always amazes me when people say that they were born gay. Looking back on my own experience, I would never say that I was "born straight." I really didn't have any interest in females until about the seventh grade. Before that time, they weren't really interesting, since they weren't interested in sports or riding bikes or anything else I liked to do.

I am not a huge fan of Neo Darwinian evolution. Nevertheless, there is some clear evidence that natural selection (and sexual selection) does act upon populations and has acted on our own species to produce racial differences.41 Natural selection postulates that those genetic mutations that favor survival and reproduction will be selected, whereas those that compromise survival and reproduction will be eliminated. Obviously, a gene or series of genes that produce non-reproducing individuals (i.e., those who express pure homosexual behavior) will be rapidly eliminated from any population. So, it would be expected that any "gay gene" would be efficiently removed from a population. However, it is possible that a gene favoring male homosexuality could "hide" within the human genome if it were located on the X-chromosome, where it could be carried by reproducing females, and not be subject to negative selection by non-reproducing males. In order to survive, the gene(s) would be expected to be associated with higher reproductive capacity in women who carry it (compensating for the generation of non-reproducing males). I can't imagine a genetic scenario in which female homosexuality would ever persist within a population.

Within the last decade, genetic analysis of heritable traits has taken a huge step forward with the advent of DNA microarray technology. Using this technology, it is possible to scan large lengths of the human genome (even an entire genome wide scanGWAS) for numerous individuals, at quite reasonable costs. This DNA microarray technology has led to the discovery of genes that are associated with complex diseases, such as Crohn's Disease, which is the topic of my research. If homosexuality truly has a genetic component, DNA microarray studies would not only definitively prove the point, but would identify specific gene(s) or loci that might be associated with those who express a homosexual orientation. The first attempt to do genome wide scans on homosexual males was done by Mustanski et al. in 2005.42 The results suggested possible linkage near microsatellite D7S798 on chromosome 7q36. However, an attempt to repeat the finding (along with ~6000 well-defined SNPs spread comparatively evenly across the human genome) failed to find any significant SNPs.43 However, a third study using Chinese subjects found a weak association at the SHH rs9333613 polymorphism of 7q36.44 A more general study, examining mate choice among different populations, found no genetic link, prompting the investigators to speculate that such choices were "culturally driven."45 The largest genome wide scan was conducted by 23andMe. 7887 unrelated men and 5570 unrelated women of European ancestry were analyzed by GWAS. Although unpublished, the data was presented at the American Society of Human Genetics annual meeting in San Francisco, showing that there were no loci associated with sexual orientation, including Xq28 on the X chromosome.46 So, the preliminary studies on possible genetic causes of homosexual orientation tends to rule out any dramatic genetic component to sexual orientation.

Why are people gay? The question of how homosexual orientation originates has been the subject of much press, with the general impression being promoted that homosexuality is largely a matter of genes, rather than environmental factors. However, if one examines the scientific literature, one finds that it's not quite as clear as the news bytes would suggest. The early studies that reported differences in the brains of homosexuals were complicated by HIV infection and were not substantiated by larger, better controlled studies. Numerous studies reported that possible hormonal differences affected homosexual orientation. However, these studies were often directly contradictory, and never actually measured any hormone levels, but just used proxies for hormonal influences, without direct evidence that the proxies were actually indicative of true hormone levels or imbalances. Twin studies showed that there likely are genetic influences for homosexuality, although similar studies have shown some genetic influences for homophobia and even opposition to abortion. Early childhood abuse has been associated with homosexuality, but, at most, only explains about 10% of those who express a homosexual orientation. The fact that sexual orientation is not constant for many individuals, but can change over time suggests that at least part of sexual orientation is actually sexual preference. Attempts to find a "gay gene" have never identified any gene or gene product that is actually associated with homosexual orientation, with studies failing to confirm early suggestions of linkage of homosexuality to region Xq28 on the X chromosome. The question of genetic influences on sexual orientation has been recently examined using DNA microarray technology, although, the results have largely failed to pinpoint any specific genes as a factor in sexual orientation.

La Gentica y la Homosexualidad: Nace la gente, homosexual?

http://www.godandscience.org/evolution/genetics_of_homosexuality.html Last updated November 25, 2013

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Are People Born Gay? Genetics and Homosexuality

Genetics – biology

Genetics

Background:

Homunculus in Sperm One question that has always intrigued us humans is Where did we come from? Long ago, Hippocrates and Aristotle proposed the idea of what they called pangenes, which they thought were tiny pieces of body parts. They thought that pangenes came together to make up the homunculus, a tiny pre-formed human that people thought grew into a baby. In the 1600s, the development of the microscope brought the discovery of eggs and sperm. Antonie van Leeuwenhoek, using a primitive microscope, thought he saw the homunculus curled up in a sperm cell. His followers believed that the homunculus was in the sperm, the father planted his seed, and the mother just incubated and nourished the homunculus so it grew into a baby. On the other hand, Regnier de Graaf and his followers thought that they saw the homunculus in the egg, and the presence of semen just somehow stimulated its growth. In the 1800s, a very novel, radical idea arose: both parents contribute to the new baby, but people (even Darwin, as he proposed his theory) still believed that these contributions were in the form of pangenes.

Modern genetics traces its beginnings to Gregor Mendel, an Austrian monk, who grew peas in a monastery garden. Mendel was unique among biologists of his time because he sought quantifiable data, and actually counted the results of his crosses. He published his findings in 1865, but at that time, people didnt know about mitosis and meiosis, so his conclusions seemed unbelievable, and his work was ignored until it was rediscovered in 1900 by a couple of botanists who were doing research on something else. Peas are an ideal organism for this type of research because they are easy to grow and it is easy to control mating.

We will be looking at the sorts of genetic crosses Mendel did, but first, it is necessary to introduce some terminology:

Monohybrid Cross and Probabilities:

A monohybrid cross is a genetic cross where only one gene/trait is being studied. P stands for the parental generation, while F1 and F2 stand for the first filial generation (the children) and second filial generation (the grandchildren). Each parent can give one chromosome of each pair, therefore one allele for each trait, to the offspring. Thus, when figuring out what kind(s) of gametes an individual can produce, it is necessary to choose one of the two alleles for each gene (which presents no problem if they are the same).

Purple Pea Flower White Pea Flower For example, a true-breeding purple-flowered plant (the dominant allele for this gene) would have the genotype PP, and be able to make gametes with either P or P alleles. A true-breeding white-flowered plant (the recessive allele for this gene) would have the genotype pp, and be able to make gametes with either p or p alleles. Note that both of these parent plants would be homozygous. If one gamete from each of these parents got together to form a new plant, that plant would receive a P allele from one parent and a p allele from the other parent, thus all of the F1 generation will be genotype Pp, they will be heterozygous, and since purple is dominant, they will look purple. What if two individuals from the F1 generation are crossed with each other (PpPp)? Since gametes contain one allele for each gene under consideration, each of these individuals could contribute either a P or a p in his/her gametes. Each of these gametes from each parent could pair with each from the other, thus yielding a number of possible combinations for the offspring. We need a way, then, to predict what the possible offspring might be. Actually, there are two ways of doing this. The first is to do a Punnett square (named after Reginald Crandall Punnett). The possible eggs from the female are listed down the left side, and there is one row for each possible egg. The possible sperm from the male are listed across the top, and there is one column for each possible sperm. The boxes at the intersections of these rows and columns show the possible offspring resulting from that sperm fertilizing that egg. The Punnett square from this cross would look like this:

Note that the chance of having a gamete with a P allele is and the chance of a gamete with a p allele is , so the chance of an egg with P and a sperm with P getting together to form an offspring that is PP is =, just like the probabilities involved tossing coins. Thus, the possible offspring include: PP, ( Pp + pP, which are the same (Pp), since P is dominant over p), so = Pp, and pp.

Another way to calculate this is to use a branching, tree diagram:

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Genetics - biology

Male-pattern hair loss – Wikipedia, the free encyclopedia

Male-pattern hair loss, also known as androgenic alopecia and male pattern baldness (MPB), is hair loss that occurs due to an underlying susceptibility of hair follicles to androgenic miniaturization. It is the most common cause of hair loss and will affect up to 70% of men and 40% of women at some point in their lifetimes. Men typically present with hairline recession at the temples and vertex balding, while women normally thin diffusely over the top of their scalps.[1][2][3] Both genetic and environmental factors play a role, and many etiologies remain unknown.

Classic androgenic hair loss in males begins above the temples and vertex, or calvaria, of the scalp. As it progresses, a rim of hair at the sides and rear of the head remains. This has been referred to as a 'Hippocratic wreath', and rarely progresses to complete baldness.[4] The Hamilton-Norwood scale has been developed to grade androgenic alopecia in males.

Female androgenic alopecia is known colloquially as "female pattern baldness", although its characteristics can also occur in males. It more often causes diffuse thinning without hairline recession; and, like its male counterpart, rarely leads to total hair loss.[5] The Ludwig scale grades severity of androgenic alopecia in females.

Animal models of androgenic alopecia occur naturally and have been developed in transgenic mice;[6]chimpanzees (Pan troglodytes); bald uakaris (Cacajao rubicundus); and stump-tailed macaques (Macaca speciosa and M. arctoides). Of these, macaques have demonstrated the greatest incidence and most prominent degrees of hair loss.[7][8]

Androgenic alopecia is typically experienced as a "moderately stressful condition that diminishes body image satisfaction".[9] However, although most men regard baldness as an unwanted and distressing experience, they usually are able to cope and retain integrity of personality.[10]

Research indicates that the initial programming of pilosebaceous units begins in utero.[11] The physiology is primarily androgenic, with dihydrotestosterone (DHT) the major contributor at the dermal papillae. Below-normal values of sex hormone-binding globulin, follicle-stimulating hormone, testosterone, and epitestosterone are present in men with premature androgenic alopecia compared to normal controls.[12] Although follicles were previously thought permanently gone in areas of complete hair loss, they are more likely dormant, as recent studies have shown the scalp contains the stem cell progenitors from which the follicles arose.[13]

Transgenic studies have shown that growth and dormancy of hair follicles are related to the activity of insulin-like growth factor at the dermal papillae, which is affected by DHT.[14]Androgens are important in male sexual development around birth and at puberty. They regulate sebaceous glands, apocrine hair growth, and libido. With increasing age,[15] androgens stimulate hair growth on the face, but suppress it at the temples and scalp vertex, a condition that has been referred to as the 'androgen paradox'.[16]

These observations have led to study at the level of the mesenchymal dermal papillae.[17][18]Types 1 and 2 5 reductase enzymes are present at pilosebaceous units in papillae of individual hair follicles.[19] They catalyze formation of the androgens testosterone and DHT, which in turn regulate hair growth.[16] Androgens have different effects at different follicles: they stimulate IGF-1 at facial hair, leading to growth, but stimulate TGF 1, TGF 2, dickkopf1, and IL-6 at the scalp, leading to catagenic miniaturization.[16] Hair follicles in anaphase express four different caspases. Tumor necrosis factor inhibits elongation of hair follicles in vitro with abnormal morphology and cell death in the bulb matrix.[20]

Studies of serum levels of IGF-1 show it to be increased with vertex balding.[21][22] Earlier work looking at in vitro administration of IGF had no effect on hair follicles when insulin was present, but when absent, caused follicle growth. The effects on hair of IGF-I were found to be greater than IGF-II.[23] Later work also showed IGF-1 signalling controls the hair growth cycle and differentiation of hair shafts,[14] possibly having an anti-apoptotic effect during the catagen phase.[24]In situ hybridization in adult human skin has shown morphogenic and mitogenic actions of IGF-1.[25] Mutations of the gene encoding IGF-1 result in shortened and morphologically bizarre hair growth and alopecia.[26] IGF-1 is modulated by IGF binding protein, which is produced in the dermal papilla.[27]

DHT inhibits IGF-1 at the dermal papillae.[28] Extracellular histones inhibit hair shaft elongation and promote regression of hair follicles by decreasing IGF and alkaline phosphatase in transgenic mice.[29] Silencing P-cadherin, a hair follicle protein at adherens junctions, decreases IGF-1, and increases TGF beta 2, although neutralizing TGF decreased catagenesis caused by loss of cadherin, suggesting additional molecular targets for therapy. P-cadherin mutants have short, sparse hair.[30]

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Male-pattern hair loss - Wikipedia, the free encyclopedia

Male Hair Loss All You Need To Know – The Belgravia Centre

Although there are a number of hair loss conditions that can affect men, the most common is Male Pattern Baldness (MPB). Other names for this condition are androgenetic alopecia and genetic hair loss. This page will concentrate primarily on this condition but will also make reference to the less widespread hair loss conditions that could be affecting you, with links to more informative pages.

Male Pattern Baldness is a genetic condition that can be passed down from either side of the family tree. So if your Father has a perfectly thick head of hair, dont think you are definitely safe (although you could be!). It is a condition caused by a bi-product of testosterone named Dihydrotestosterone, or DHT. DHT attaches to the hair follicles and causes them to shrink over time, which causes the hair to become thinner and thinner until some men become totally bald on the top of the head.

This is a very good question, and although the answer might seem obvious, many men do not identify their hair loss until it has become fairly advanced, which could be too late to achieve a full recovery. The reasons men do not identify their own hair loss are usually down to simple denial, or because the process is very slow and it is something that they simply might not notice. At the opposite end of the scale, many men worry about hair loss when they have no reason to worry.

The best ways to know if you are losing your hair are:

MPB is in fact easy to identify even for somebody with no clinical experience as it only affects hair on the top of the scalp and not the sides, causing a horseshoe-shaped pattern of hair loss. There are a number of different common patterns of hair loss a receding hairline, a thinning crown, or general thinning spread over the top area of the head. You can read more about these below. MPB never affects the sides or back of the hair.

There are a number of options available for treating Male Pattern Baldness, including clinically proven medications, laser devices and hair restoration surgery. There are also numerous products out there that have no clinical efficacy, so it is easy to waste time and money whilst your hair continues to shed. It is therefore very important that you carry out the necessary research before deciding how you are going to treat your hair loss. The good news is that unless you have lost all or most of your hair, there is a solution out there for you, whether it be a medical solution, a surgical one, or a combination of the two.

Our comprehensive hair loss treatment guide walks you through all the most effective options available for treating hair loss and also gives you an in-depth look at the products that may not be worth using.

hair loss treatment guide

This depends on a number of factors. Firstly, the condition causing your hair loss if you have a temporary hair loss condition (which is unusual in men) then the answer may be no. Please refer to our list of other hair loss conditions below if your problem doesnt appear to be MPB.

Assuming your condition is Male Pattern Baldness, the extent of your eventual hair loss really depends. Those men who have a very early or aggressive onset of MPB are more likely to lose their hair more extensively or at a faster rate, which could result in baldness at an early age. We see men who begin to lose their hair at 18 years old (or sometimes earlier). These men will of course be the ones most likely to reach eventual baldness, sometimes at a fairly early age (mid-twenties). Whereas some men only begin to see signs of thinning in their mid-to-late twenties, or even later. These men are much less likely to experience eventual baldness and may just have thin hair by the time they reach old age.

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Male Hair Loss All You Need To Know - The Belgravia Centre

The Genetics of Male Infertility – The Turek Clinic

Your Expert in Male Fertility & Sexual Health

High technology approaches to fertility, including ICSI, are really a two edged sword: they allow us to treat severe male infertility, but they may alter natural selection in that decisions regarding sperm and eggs are made in the laboratory and not by nature.

Dr. Paul Turek

Among the 15% of couples who experience infertility, about 40% of the time the infertility is due to male factors. About half of male infertility cases are due to defined reasons, including varicocele, infection, hormone imbalances, exposures such as drugs or medications, x-rays, tobacco use and hot tubs, blockage of the reproductive tract ducts, and previous surgery that has left scarring. Another cause of male infertility that has been underestimated in the past, but is now gaining in importance is genetic infertility. The reason for its increased importance is that our knowledge about genetics is growing so quickly. Men who may have had unexplained infertility in the past may now be diagnosed with genetic causes of infertility through recently available testing. In fact, this field is progressing so quickly that genetic infertility has already become one of the most commonly diagnosed reasons for male infertility.

Developed in the early 1990s, assisted reproduction in the form of IVF and ICSI (intracytoplasmic sperm injection) is a revolutionary laboratory technique in which a single sperm is placed directly inside an egg for fertilization. This technique has opened the door to fertility for men who formerly had few available treatment options, as it allows men who were previously considered severely infertile or sterile the possibility of fatherhood. However, with ICSI sperm are chosen by laboratory technicians and not by nature and because of this, it is not clear what barriers to natural selection are altered. Thus, along with this technology comes the possibility of passing on to a child certain genetic issues that may have caused the fathers infertility, or even more severe conditions. Another reason to know whether male

Infertility is genetic or not is because classic treatments such as varicocele repair or medications given to improve male infertility. In fact, Dr Turek was one of the first to publish on this issue, showing that varicocele repair was not effective in improving fertility in men with genetic infertility. Because he recognized these issues early on, Dr. Turek, while at UCSF in 1997, founded the first formal genetic counseling and testing program for infertility in the U.S. Called the Program in the Genetics of Infertility (PROGENI), Dr. Tureks program has helped over 2000 patients at risk for genetic infertility to navigate the decision-making waters that surround this condition.

Men with infertility should be seen by a urologist for a thorough medical history, physical examination, and appropriate medical testing. If genetic infertility is a possibility, then a genetic counselor can help couples understand the possible reasons, offer appropriate genetic testing, and discuss the complex emotional and medical implications of the test results. The approach taken early on by Dr. Turek is outlined in Figure 1. Just like the medical diagnosis from a urologist or fertility specialist, information about family history plays a critical role in genetic risk assessment. This approach to genetic evaluation, termed non-prescriptive, has been the corner- stone of Dr. Tureks critically acclaimed clinical program that now has over a dozen publications contributing to our current knowledge in the field. It is important to note that a lack of family history of infertility or other medical problems does not eliminate or reduce the risk of genetic infertility. In fact, a family history review will often be unremarkable. However, family history can provide crucial supporting in- formation toward making a genetic diagnosis (such as a family history of recurrent miscarriages or babies born with problems). Dr. Turek has published that having a genetic counselor obtain family history information is much more accurate than simply giving patients a written questionnaire to fill out and bring to their visit. A genetic counselor can also discuss appropriate genetic testing options and review the test results in patients in a meaningful way.

When speaking to Dr. Tureks genetic counselor about genetic testing, keep in mind that he or she will not tell you what to do. Genetic counselors are trained to provide information, address questions and concerns, and support you in the decision making process. A genetic counselor does not assume which decisions are most appropriate for you.

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The Genetics of Male Infertility - The Turek Clinic

WHO | Gender and Genetics

Genetic Components of Sex and Gender

Humans are born with 46 chromosomes in 23 pairs. The X and Y chromosomes determine a persons sex. Most women are 46XX and most men are 46XY. Research suggests, however, that in a few births per thousand some individuals will be born with a single sex chromosome (45X or 45Y) (sex monosomies) and some with three or more sex chromosomes (47XXX, 47XYY or 47XXY, etc.) (sex polysomies). In addition, some males are born 46XX due to the translocation of a tiny section of the sex determining region of the Y chromosome. Similarly some females are also born 46XY due to mutations in the Y chromosome. Clearly, there are not only females who are XX and males who are XY, but rather, there is a range of chromosome complements, hormone balances, and phenotypic variations that determine sex.

The biological differences between men and women result from two processes: sex determination and differentiation.(3) The biological process of sex determination controls whether the male or female sexual differentiation pathway will be followed. The process of biological sex differentiation (development of a given sex) involves many genetically regulated, hierarchical developmental steps. More than 95% of the Y chromosome is male-specific (4) and a single copy of the Y chromosome is able to induce testicular differentiation of the embryonic gonad. The Y chromosome acts as a dominant inducer of male phenotype and individuals having four X chromosomes and one Y chromosome (49XXXXY) are phenotypically male. (5) When a Y chromosome is present, early embryonic testes develop around the 10th week of pregnancy. In the absence of both a Y chromosome and the influence of a testis-determining factor (TDF), ovaries develop.

Gender, typically described in terms of masculinity and femininity, is a social construction that varies across different cultures and over time. (6) There are a number of cultures, for example, in which greater gender diversity exists and sex and gender are not always neatly divided along binary lines such as male and female or homosexual and heterosexual. The Berdache in North America, the faafafine (Samoan for the way of a woman) in the Pacific, and the kathoey in Thailand are all examples of different gender categories that differ from the traditional Western division of people into males and females. Further, among certain North American native communities, gender is seen more in terms of a continuum than categories, with special acknowledgement of two-spirited people who encompass both masculine and feminine qualities and characteristics. It is apparent, then, that different cultures have taken different approaches to creating gender distinctions, with more or less recognition of fluidity and complexity of gender.

Sex Chromosome Abnormalities Turner syndrome XXX Females Klinefelter Syndrome XYY Males

Typical sexual development is the result of numerous genes, and mutation in any of these genes can result in partial or complete failure of sex differentiation. These include mutations or structural anomalies of the SRY region on the Y chromosome resulting in XY gonadal dysgenesis, XX males, or XY females; defects of androgen biosynthesis or androgen receptors, and others.

Hermaphroditism Congenital Adrenal Hyperplasia Androgen Insensitivity Syndrome

The issues of gender assignment, gender verification testing, and legal definitions of gender are especially pertinent to a discussion on the ELSI of gender and genetics. These practices, however, are misnomers as they actually refer to biological sex and not gender. Such a discrepancy is highlighted by the existence of intersex individuals whose psychosexual development and gender sometimes do not match the biological sex assigned to them as infants. In this report the term sex will be used where the practice refers to biological sex and not the more social construct of gender.

Gender Assignment of Intersex Infants and Children Legal Definitions of Gender

Chromosomes are the structures that carry genes which in turn transmit hereditary characteristics from parents to offspring. Humans have 23 pairs of chromosomes, one half of each pair inherited from each parent. The Y chromosome is small, carries few genes, and has abundant repetitive sequence, while the X chromosome is more autosome-like in form and content. (14)Despite being relatively gene-poor overall due to reduced recombination, the X and Y sex chromosomes are enriched for genes that relate to sexual development. (15)

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WHO | Gender and Genetics

Male – Wikipedia, the free encyclopedia

A male () organism is the physiological sex that produces sperm. Each spermatozoon can fuse with a larger female gamete, or ovum, in the process of fertilization. A male cannot reproduce sexually without access to at least one ovum from a female, but some organisms can reproduce both sexually and asexually. Most male mammals, including male humans, have a Y chromosome, which codes for the production of larger amounts of testosterone to develop male reproductive organs.

Not all species share a common sex-determination system. In most animals, including humans, sex is determined genetically, but in some species it can be determined due to social, environmental or other factors. For example, Cymothoa exigua changes sex depending on the number of females present in the vicinity. [1]

The existence of two sexes seems to have been selected independently across different evolutionary lineages (see Convergent Evolution). The repeated pattern is sexual reproduction in isogamous species with two or more mating types with gametes of identical form and behavior (but different at the molecular level) to anisogamous species with gametes of male and female types to oogamous species in which the female gamete is very much larger than the male and has no ability to move. There is a good argument that this pattern was driven by the physical constraints on the mechanisms by which two gametes get together as required for sexual reproduction.[2]

Accordingly, sex is defined operationally across species by the type of gametes produced (i.e.: spermatozoa vs. ova) and differences between males and females in one lineage are not always predictive of differences in another.

Male/female dimorphism between organisms or reproductive organs of different sexes is not limited to animals; male gametes are produced by chytrids, diatoms and land plants, among others. In land plants, female and male designate not only the female and male gamete-producing organisms and structures but also the structures of the sporophytes that give rise to male and female plants.

A common symbol used to represent the male sex is the Mars symbol, (Unicode: U+2642 Alt codes: Alt+11)a circle with an arrow pointing northeast. The symbol is identical to the planetary symbol of Mars. It was first used to denote sex by Carolus Linnaeus in 1751. The symbol is often called a stylized representation of the Roman god Mars' shield and spear. According to Stearn, however, all the historical evidence favours that it is derived from , the contraction of the Greek name for the planet, Thouros.[3]

The sex of a particular organism may be determined by a number of factors. These may be genetic or environmental, or may naturally change during the course of an organism's life. Although most species with male and female sexes have individuals that are either male or female, hermaphroditic animals, such as worms, have both male and female reproductive organs.

Most mammals, including humans, are genetically determined as such by the XY sex-determination system where males have an XY (as opposed to XX) sex chromosome. It is also possible in a variety of species, including human beings, to be XXY or have other intersex/hermaphroditic qualities. These qualities are widely reported to be as common as redheadedness (about 2% of the population).[4] During reproduction, a male can give either an X sperm or a Y sperm, while a female can only give an X egg. A Y sperm and an X egg produce a male, while an X sperm and an X egg produce a female.

The part of the Y-chromosome which is responsible for maleness is the sex-determining region of the Y-chromosome, the SRY. The SRY activates Sox9, which forms feedforward loops with FGF9 and PGD2 in the gonads, allowing the levels of these genes to stay high enough in order to cause male development;[5] for example, Fgf9 is responsible for development of the spermatic cords and the multiplication of Sertoli cells, both of which are crucial to male sexual development.[6]

The ZW sex-determination system, where males have a ZZ (as opposed to ZW) sex chromosome may be found in birds and some insects (mostly butterflies and moths) and other organisms. Members of the insect order Hymenoptera, such as ants and bees, are often determined by haplodiploidy, where most males are haploid and females and some sterile males are diploid.[citation needed]

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Male - Wikipedia, the free encyclopedia

Understanding Genetics

-A curious adult from California

August 6, 2004

What a fun question! This sort of thing has been bothering me too lately. The usual statistic is that all people are 99.9% the same. But is that true for men and women?

And what about our similarity to other animals? We are really only about 80% the same as a mouse at the genetic level so men and women are clearly more similar to each other than to mice. But what about chimpanzees? If people really are 98.7% the same as a chimpanzee, are male chimpanzees closer genetically to men than men are to women?

As you know, men have an X and a Y chromosome and women have two X chromosomes. So besides the usual 0.1% (or 3.2 million base pair) difference between people, men and women differ by the presence of the Y chromosome.

The Y chromosome is a tiny thing; it is about 59 million base pairs long and has only 78 genes. If we look at base pairs, the difference between men and women would be 59 million divided by 3.2 billion or about 1.8%. This translates to men and women being 98.2% the same.

Men and women are actually a bit more similar as the Y chromosome has about 5% of its DNA sequences in common with the X chromosome. This would change the number to 98.4% the same.

If the 98.7% number for chimp-human similarity is right, then by this measure, men and women are less alike than are female chimps and women. (More recent data suggests that chimps may be 95% instead of 98.7% the same, but this is still up in the air.)

Now if we look at the gene level instead of at the base pair level, men and women become much more similar. If we assume 30,000 total genes, then men and women are about 99.7% the same instead of 98.4%. (I haven't been able to find a good number for how many genes chimpanzees and humans share.)

So is the bottom line that men and male chimps have more in common than men and women? Of course not. If we take a closer look, we see some of the dangers of looking at raw percentages instead of individual changes.

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Understanding Genetics

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